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Martins EF, Cappello CH, Shinjo SK, Appenzeller S, de Souza JM. Idiopathic Inflammatory Myopathies: Recent Evidence Linking Pathogenesis and Clinical Features. Int J Mol Sci 2025; 26:3302. [PMID: 40244108 PMCID: PMC11989767 DOI: 10.3390/ijms26073302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Idiopathic inflammatory myopathies are rare and complex representatives of systemic connective tissue diseases. Described initially as only two entities, recent advances in molecular and imaging techniques now divide them into many subtypes, each with unique pathogenesis and clinical phenotypes. Dermatomyositis and its juvenile form are the most prevalent subtypes and are characterized by systemic vasculopathy and humoral autoimmunity. Genetic predisposition and environmental triggers initiate immune tolerance breakdown, leading to autoantibody production, complement activation, and tissue damage. Anti-synthetase syndrome primarily affects the lungs, where immune responses to aminoacyl-RNA synthetases drive vasculopathy, lung inflammation, and fibrosis. Immune-mediated necrotizing myopathies are muscle-specific, with autoantibodies inducing fiber necrosis and atrophy. Lastly, sporadic inclusion body myositis is a slowly progressive myopathy in which dysfunctional protein handling and autophagy are more important pathogenic elements than muscle inflammation itself. The expanding body of basic science evidence can be overwhelming, making it challenging to connect pathogenic mechanisms to clinical manifestations. This review aims to address this challenge by presenting recent insights into myositis pathogenesis from a practical perspective, reinforcing the links between basic science and clinical semiology.
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Affiliation(s)
- Eunice Fragoso Martins
- Department of Internal Medicine, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-881, Brazil
- Post-Graduate Program in Medical Sciences, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-887, Brazil
| | - Carla Helena Cappello
- Department of Orthopedics, Rheumatology and Traumatology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-887, Brazil
- Post-Graduate Program in Child and Adolescent Health, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-888, Brazil
| | - Samuel Katsuyuki Shinjo
- Division of Rheumatology, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
| | - Simone Appenzeller
- Department of Orthopedics, Rheumatology and Traumatology, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-887, Brazil
| | - Jean Marcos de Souza
- Department of Internal Medicine, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-881, Brazil
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Ardalan K, Marques MC, Cella D, Curran ML, Gray EL, Lee J, Fahey KJ, Wolfe ML, Pachman LM, Chang RW. Psychometric properties of patient-reported outcomes measurement information system (PROMIS) fixed short forms in Juvenile Myositis. Semin Arthritis Rheum 2025; 71:152649. [PMID: 39933204 PMCID: PMC11890175 DOI: 10.1016/j.semarthrit.2025.152649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 01/08/2025] [Accepted: 01/22/2025] [Indexed: 02/13/2025]
Abstract
OBJECTIVES Assess reliability and validity of Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric self-report and parent-proxy report fixed short forms in juvenile myositis (JM). METHODS Children with JM (8-17yo) and parents of 5-17 yo JM patients completed PROMIS measures (Physical Function, Pain Interference, Fatigue, Emotional Distress), PedsQL Generic Core scales and Rheumatology Module (PedsQL-GC/-RM). Internal consistency reliability was assessed via Cronbach's alpha. Patient-parent agreement was assessed via intraclass correlations (ICC). Concurrent and construct validity were assessed via Spearman's correlations between PROMIS versus PedsQL-GC/-RM and clinical/lab data respectively. Known-groups validity was assessed by comparing PROMIS T-scores between clinically distinct JM patients. RESULTS We enrolled 75 JM participants, with 57 administered self-report and all 75 administered parent-proxy report measures per participant age. PROMIS measures were feasible (>96% completion), with high internal consistency reliability (Cronbach's alpha >0.8). Patient-parent assessments demonstrated moderate agreement (ICC >0.5) for Mobility, Upper Extremity, and Fatigue domains, and smaller correlations (ICC 0.41-0.47) as expected for Pain Interference, Depressive Symptoms, and Anxiety. Concurrent validity was demonstrated by moderate correlation (Spearman's rho >0.5) for all but 1 hypothesized relationships of PROMIS and PedsQL-GC/-RM domains. Although low disease activity and small sample size limited statistical power, construct validity and known-groups validity were demonstrable for multiple PROMIS pediatric self-report and parent-proxy report measures. CONCLUSION PROMIS measures show evidence of reliability and validity in JM. Child and parent reports differ sufficiently to suggest both should be collected. PROMIS measures can be considered for clinical and research use in JM.
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Affiliation(s)
- Kaveh Ardalan
- Division of Pediatric Rheumatology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA; Division of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA; Departments of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Mariana C Marques
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David Cella
- Departments of Medical Social Sciences, Neurology, and Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Megan L Curran
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Elizabeth L Gray
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jungwha Lee
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Kyle J Fahey
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Madison L Wolfe
- Division of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Lauren M Pachman
- Division of Rheumatology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, The Cure JM Center of Excellence, The Stanley Manne Children's Research Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Rowland W Chang
- Departments of Preventive Medicine, Medicine, and Physical Medicine & Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Li G, Yan X, Luo C, An Y, Zhang Z, Tang X, Zhao X, Yang X. Clinical and genetic analysis of macrophage activation syndrome complicating juvenile idiopathic inflammatory myopathies. Pediatr Res 2025; 97:1031-1039. [PMID: 39181985 DOI: 10.1038/s41390-024-03515-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Macrophage activation syndrome (MAS) is a serve complication of juvenile idiopathic inflammatory myopathies (JIIMs). This study delineates the clinical manifestations and genetic underpinnings of JIIM-MAS patients. METHODS We retrospectively analysed clinical and UNC13D gene from JIIM patients admitted to our centre between 2011 and 2021 to identify cases of MAS. Additionally, a literature review summarising reported cases of JIIMs and MAS was performed. RESULTS Of 773 JIIM patients, 10 (1.3%) were diagnosed with MAS. All patients presented with persistent fever and hyperferritinaemia. Seventy percent of patients met the HLH-2004 criteria, while 90% met the 2016 sJIA-MAS criteria. Most patients received combined treatment of corticosteroids and immunosuppressants. UNC13D gene analysis was performed in six patients. A homozygous pathogenic mutation (c.2588G>A) was detected in one patient with recurrent MAS, and twenty-eight single-nucleotide polymorphisms (SNPs) were detected. Eighty percent of patients exhibiting a consistent combination of ten SNPs compared to JIIM patients without MAS (35%). CONCLUSION MAS is an early and often overlooked complication of JIIMs. The 2016 sJIA-MAS criteria may facilitate early diagnosis. Combined corticosteroid and immunosuppressant therapy prove effective. An increased prevalence of UNC13D gene polymorphisms was observed in JIIM-MAS patients, highlighting the necessity for further investigations. IMPACT This study aimed to delineate the clinical manifestations and genetic underpinnings of macrophage activation syndrome (MAS) in ten patients with juvenile idiopathic inflammatory myopathies (JIIMs). MAS has been recognised as a complication of JIIMs. However, only a few case reports provide comprehensive descriptions of MAS in JIIM patients, and there are few reports related to UNC13D mutations in these patients. This article offers single-centre clinical insights to enhance the identification and management of MAS in JIIM patients, while also highlighting the potential association between MAS occurrence and UNC13D gene polymorphisms.
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Affiliation(s)
- Guangzhao Li
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Xin Yan
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Chong Luo
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Yunfei An
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Zhiyong Zhang
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Xuemei Tang
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Xiaodong Zhao
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China
| | - Xi Yang
- Children's Hospital of Chongqing Medical University, Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, China.
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Kim H. Juvenile Dermatomyositis: Updates in Pathogenesis and Biomarkers, Current Treatment, and Emerging Targeted Therapies. Paediatr Drugs 2025; 27:57-72. [PMID: 39425894 PMCID: PMC11774970 DOI: 10.1007/s40272-024-00658-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2024] [Indexed: 10/21/2024]
Abstract
Juvenile dermatomyositis is a rare systemic inflammatory autoimmune disease involving muscle, skin, and vessels. Most patients do not fully respond to initial therapy, instead having a chronic refractory or polycyclic disease course. Pathogenesis is not completely understood, but immune cell dysregulation, particularly of B cells, mitochondrial dysfunction, changes in neutrophils and neutrophil extracellular traps (NETs), and increased type I and type II interferon (IFN) signaling have been described. There are limited randomized controlled trials of drugs in juvenile dermatomyositis (JDM), and treatment is largely based on lower-quality data such as case series, retrospective studies, and open-label prospective studies. These data have been compiled into expert recommendations or consensus treatment plans, which help guide therapy. While initial therapy is more standard with most including corticosteroids (high-dose oral and/or pulse intravenous methylprednisolone) and methotrexate, for refractory patients, guidelines are more varied with multiple options or combinations, including biologic therapies. There is a clear need for more efficacious and personalized therapy in JDM. Emerging treatment options worthy of further study in JDM include targeting IFN-signaling (JAK, IFNAR1, IFN beta), B-cells (CD20, CD19, BAFF, TACI, CD38, BCMA) including Chimeric Antigen Receptor (CAR)-T cell therapy, mitochondrial dysfunction, and NETs.
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Affiliation(s)
- Hanna Kim
- National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
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Maccora I, Brunner HI, Cassedy A, Altaye M, Quinlan‐Waters M, Lovell DJ, Grom A, Angeles‐Han ST. Achieving Medication-Free Remission in Patients With Juvenile Dermatomyositis. ACR Open Rheumatol 2025; 7:e11751. [PMID: 39707697 PMCID: PMC11707262 DOI: 10.1002/acr2.11751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 09/03/2024] [Indexed: 12/23/2024] Open
Abstract
OBJECTIVE Prognostic factors associated with medication discontinuation in children with juvenile dermatomyositis (JDM) remain largely elusive. We aim to identify the predictors of medication-free remission (MFR) in children with JDM. METHODS In this retrospective study, patients diagnosed with JDM according to Peter & Bohan criteria and followed for ≥18 months at a tertiary care center from 2006 through 2022 were included. Data extracted included demographics, physical examination, laboratory results, and medications. MFR was defined as inactive JDM after discontinuation of all systemic immunosuppressives for ≥6 months, in line with international consensus guidelines for trials of therapies in idiopathic inflammatory myopathies. A two-sided P < 0.05 was considered statistically significant. RESULTS Of 55 patients with JDM (63.6% female, age median [interquartile range (IQR)] 6 [3.5-12] years), 29 (52.7%) achieved MFR after a median (IQR) of 33 (22.5-55.2) months. MFR was more common in those who were younger at JDM diagnosis (median 5 vs 8 years, P = 0.008), had early resolution of disease activity (median 11 vs 18 months, P < 0.001), and presented with Gottron papules (χ2 = 5.25; P = 0.022) and elevated lactate dehydrogenase (χ2 = 4.82, P = 0.028). Diagnosis of JDM before 5 years old (odds ratio 4.5, 95% confidence interval [CI] 1.2-16.7) was the only predictor of MFR in our multivariate model (area under the curve 0.65, 95% CI 0.53-0.76). CONCLUSION Half of our patients with JDM achieved MFR. Age at JDM diagnosis may be an important predictor of achieving MFR.
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Affiliation(s)
- Ilaria Maccora
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, and University of Florence and Meyer Children's Hospital IRCCSFlorenceItaly
| | - Hermine I. Brunner
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
| | - Amy Cassedy
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
| | - Mekibib Altaye
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
| | | | - Daniel J. Lovell
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
| | - Alexei Grom
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
| | - Sheila T. Angeles‐Han
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiOhio
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Allameen NA, Ramos-Lisbona AI, Wedderburn LR, Lundberg IE, Isenberg DA. An update on autoantibodies in the idiopathic inflammatory myopathies. Nat Rev Rheumatol 2025; 21:46-62. [PMID: 39609638 DOI: 10.1038/s41584-024-01188-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Myositis-specific autoantibodies (MSAs) have become pivotal biomarkers for idiopathic inflammatory myopathies and have revolutionized understanding of the heterogeneous disease spectrum that affects both adults and children. The discovery and characterization of MSAs have substantially enhanced patient stratification based on clinical phenotype, thereby facilitating more precise diagnosis and ultimately improving management strategies. Advances in immunoassay technologies in the past 20 years have further propelled the field forward, enabling the detection of a growing repertoire of autoantibodies with high specificity and sensitivity; however, evolving research over the past decade has revealed that even within antibody-defined subsets, considerable clinical diversity exists, suggesting a broader spectrum of disease manifestations than previously acknowledged. Challenges persist, particularly among patients who are seronegative, where the failure to identify certain rare MSAs stems from the use of diverse detection methodologies and inadequate consensus-guided standardization and validation protocols. Bridging these diagnostic gaps is crucial for optimizing patient care and refining prognostic stratification in idiopathic inflammatory myopathies.
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Affiliation(s)
- Nur Azizah Allameen
- Rheumatology Service, Department of Medicine, Woodlands Health, Singapore, Singapore
| | | | - Lucy R Wedderburn
- Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- UK Centre for Adolescent Rheumatology Versus Arthritis at UCL, University College Hospital and Great Ormond Street Children's Hospital, London, UK
- Department of Rheumatology, Great Ormond Street Children's Hospital, London, UK
| | - Ingrid E Lundberg
- Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology, Dermatology and Rheumatology, Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
| | - David A Isenberg
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, UK.
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Baluta S, Stojkic I, Driest K, Schutt C. Case Report: IVIG causing bilateral papilledema and increased intracranial hypertension in patients with anti-TIF-1γ antibody-positive JDM. Front Pediatr 2024; 12:1433481. [PMID: 39606693 PMCID: PMC11598693 DOI: 10.3389/fped.2024.1433481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 10/15/2024] [Indexed: 11/29/2024] Open
Abstract
Juvenile dermatomyositis is a systemic autoimmune disease characterized by progressive proximal muscle weakness, pathognomonic rashes, and often the presence of myositis-specific antibodies. Consensus treatment plans for pediatric patients with juvenile dermatomyositis recommend steroids and methotrexate as initial therapy. Patients with anti-transcription intermediary factor 1 gamma (anti-TIF-1γ) antibodies tend to have more refractory disease requiring more aggressive treatment with intravenous immunoglobulin, which is typically well tolerated. We describe two pediatric patients diagnosed with anti-TIF-1γ antibody-positive juvenile dermatomyositis who developed persistent increased intracranial pressure following intravenous immunoglobulin treatment. These cases suggest a potential association between treatment with intravenous immunoglobulin and increased intracranial pressure, a side effect that is not readily known. The shared anti-TIF-1γ positivity in both patients may suggest a possible concern for intracranial hypertension among juvenile dermatomyositis patients with this myositis-specific antibody.
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Affiliation(s)
- Sarah Baluta
- Department of Pediatrics, Golisano Children’s Hospital, University of Rochester, Rochester, NY, United States
| | - Ivana Stojkic
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Kyla Driest
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Christina Schutt
- Department of Pediatrics, Golisano Children’s Hospital, University of Rochester, Rochester, NY, United States
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Tarvin SE, Sherman MA, Kim H, Balmuri N, Brown AG, Chow A, Gewanter HL, de Guzman MM, Huber AM, Kim S, Klein-Gitelman MS, Perron MM, Robinson AB, Sabbagh SE, Savani S, Shenoi S, Spitznagle J, Stingl C, Syverson G, Tory H, Spencer C. Childhood Arthritis and Rheumatology Research Alliance Biologic Disease-Modifying Antirheumatic Drug Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis. Arthritis Care Res (Hoboken) 2024; 76:1532-1539. [PMID: 38937134 DOI: 10.1002/acr.25393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 06/04/2024] [Accepted: 06/13/2024] [Indexed: 06/29/2024]
Abstract
OBJECTIVE The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CONCLUSION CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.
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Affiliation(s)
| | - Matthew A Sherman
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
| | - Hanna Kim
- National Institute of Arthritis Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
| | | | - Amanda G Brown
- University of Arkansas for Medical Sciences/Arkansas Children's Hospital, Little Rock
| | - Albert Chow
- Loma Linda Children's Hospital, Loma Linda, California
| | - Harry L Gewanter
- Children's Hospital of Richmond at Virginia Commonwealth University Health
| | | | - Adam M Huber
- IWK Health, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Susan Kim
- University of California, San Francisco
| | - Marisa S Klein-Gitelman
- Ann & Robert Lurie Children's Hospital of Chicago and Northwestern University, Chicago, Illinois
| | | | | | | | - Sonia Savani
- Medical University of South Carolina, Charleston
| | - Susan Shenoi
- University of Washington and Seattle Children's Hospital and Research Center, Seattle
| | - Jacob Spitznagle
- University of Washington and Seattle Children's Hospital and Research Center, Seattle
| | | | | | - Heather Tory
- Connecticut Children's Medical Center, Hartford, and University of Connecticut School of Medicine, Farmington
| | - Charles Spencer
- Batson Children's Hospital, University of Mississippi Medical Center, Jackson
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Tsuji H, Nakashima R, Yasumi T, Sasai T, Ichimura Y, Shirakashi M, Onizawa H, Hiwa R, Kitagori K, Akizuki S, Onishi A, Yoshifuji H, Tanaka M, Okiyama N, Mimori T, Morinobu A. Differences in the autoantibody phenotypes and long-term outcomes between juvenile- and adult-idiopathic inflammatory myopathies. Semin Arthritis Rheum 2024; 68:152530. [PMID: 39142036 DOI: 10.1016/j.semarthrit.2024.152530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 07/11/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024]
Abstract
OBJECTIVE To investigate differences in autoantibodies, clinical features, and long-term outcomes between juvenile-idiopathic inflammatory myopathy (IIM) and adult-IIM METHODS: Autoantibodies, clinical characteristics, and drug-free conditions for a maximum of 20 years were retrospectively analyzed in 320 Japanese IIM patients (juvenile-IIM, n = 34; adult-IIM, n = 286) using the Kyoto University Registry. RESULTS Autoantibodies observed in juvenile-IIM were anti-TIF1-γ (15 %), anti-MDA-5 (15 %), anti-ARS (9 %), and anti-NXP-2 (6 %). Those observed in adult-IIM were anti-ARS (32 %), anti-MDA-5 (23 %), anti-TIF1-γ (8 %), anti-SRP (8 %), anti-Mi-2 (2 %), and anti-NXP-2 (1 %). The cumulative drug-free condition rate was higher in juvenile-IIM than in adult-IIM up to 20 years (juvenile-IIM vs. adult-IIM, 34 % vs. 18 %, p = 0.0016). Anti-TIF1-γ was associated with lesser muscle symptoms (60 % vs. 90 %), malignancy (0 % vs. 57 %), and glucocorticoid use (40 % vs. 86 %) in juvenile-IIM compared to adult-IIM, while juvenile-IIM more achieved drug-free conditions (60 % vs. 25 %). Both juvenile-IIM and adult-IIM with anti-MDA-5 demonstrated a high frequency of amyopathic dermatomyositis, interstitial lung disease (ILD), and multi-immunosuppressive therapy, with high drug-free conditions (50 % vs. 49 %). Both juvenile-IIM and adult-IIM with anti-ARS showed frequent skin rashes, muscle symptoms, and ILD, frequent need for multi-immunosuppressive therapy, and low drug-free condition rates (0 % vs. 3 %). Both juvenile-IIM and adult-IIM with anti-NXP-2 showed frequent skin rashes and muscle symptoms, low ILD frequency, and frequent use of methotrexate and glucocorticoids, which did not achieve drug-free conditions (0 % vs. 0 %). CONCLUSIONS Drug-free condition was achieved more frequently in juvenile-IIM patients than adult-IIM patients. Specific autoantibodies were associated with different clinical characteristics and outcomes between juvenile-IIM and adult-IIM.
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Affiliation(s)
- Hideaki Tsuji
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
| | - Ran Nakashima
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Takahiro Yasumi
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Tsuneo Sasai
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yuki Ichimura
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Mirei Shirakashi
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hideo Onizawa
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Ryosuke Hiwa
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Koji Kitagori
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shuji Akizuki
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akira Onishi
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hajime Yoshifuji
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Masao Tanaka
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Naoko Okiyama
- Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Akio Morinobu
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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Kobayashi I. Advances in Juvenile Dermatomyositis: Pathophysiology, Diagnosis, Treatment and Interstitial Lung Diseases-A Narrative Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1046. [PMID: 39334579 PMCID: PMC11430821 DOI: 10.3390/children11091046] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024]
Abstract
Juvenile idiopathic inflammatory myopathy (JIIM) is a rare systemic autoimmune disease characterized by skeletal muscle weakness with or without a skin rash. Juvenile dermatomyositis (JDM) is the most common subtype of JIIM, accounting for 80% of JIIM. Recent studies identified several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). Each MSA or MAA is associated with distinct clinical features and outcomes, although there are several differences in the prevalence of MSA/MAA and autoantibody-phenotype relationships between age and ethnic groups. Histopathological studies have revealed critical roles of type I interferons and vasculopathy in the development of JDM. Serological classification mostly corresponds to clinicopathological classification. Novel therapeutic agents, such as biologics and Janus kinase inhibitors (JAKi), have been developed; however, to date, there is a lack of high-level evidence. As advances in treatment have reduced the mortality rate of JIIM, recent studies have focused on medium- and long-term outcomes. However, rapidly progressive interstitial lung disease (RP-ILD) remains a major cause of death in anti-melanoma differentiation gene 5 autoantibody-positive JDM. Early diagnosis and intervention using a multi-drug regimen is critical for the treatment of RP-ILD. Rituximab and JAKi may reduce mortality in patients with JDM-associated RP-ILD refractory to conventional therapy.
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Affiliation(s)
- Ichiro Kobayashi
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, 3-40 Hiragishi 1-6, Toyohira-ku, Sapporo 060-0931, Japan
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11
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Carriquí-Arenas S, Mosquera JM, Quesada-Masachs E, López M, Clemente D, Boteanu A, Udaondo C, de Inocencio J, Nieto JC, Riancho L, Núñez E, Sánchez-Manubens J, Lirola MJ, Roldán R, Camacho M, Martínez M, Medrano M, Alcañiz P, Antón J, Iglesias E. Clinical characteristics and prognostic factor in juvenile dermatomyositis: data of the Spanish registry. Pediatr Rheumatol Online J 2024; 22:66. [PMID: 39039532 PMCID: PMC11265073 DOI: 10.1186/s12969-024-00999-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 06/16/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Juvenile Dermatomyositis (JDM) is the most common chronic idiopathic inflammatory myopathy in children. The diagnosis is clinical. Baseline laboratory and complementary studies trace the phenotype of these patients. The objective of this study was to describe epidemiological, clinical and laboratory characteristics at diagnosis of JDM patients included in the Spanish JDM registry, as well as to identify prognostic factors on these patients. METHODS We retrospectively reviewed clinical features, laboratory tests, and complementary studies at diagnosis of JDM patients included on the Spanish JDM registry. These data were analyzed to assess whether there was a relationship with the development of complications and time to disease inactivity. RESULTS One hundred and sixteen patients from 17 Spanish paediatric rheumatology centres were included, 76 girls (65%). Median age at diagnosis was 7.3 years (Interquartile range (IQR) 4.5-10.2). All patients had pathognomonic skin lesions at the beginning of the disease. Muscle weakness was present in 86.2%. Median Childhood Muscle Assessment Scale was 34 (IQR 22-47). Twelve patients (34%) had dysphagia and 3,5% dysphonia. Anti-p155 was the most frequently detected myositis specific antibody, followed by anti-MDA5. Twenty-nine patients developed calcinosis and 4 presented with macrophage activation syndrome. 70% reached inactivity in a median time of 8.9 months (IQR 4.5-34.8). 41% relapsed after a median time of 14.4 months (IQR 8.6-22.8) of inactivity. Shorter time to treatment was associated with better prognosis (Hazard ratio (HR) = 0.95 per month of evolution, p = 0.02). Heliotrope rash at diagnosis correlates with higher risk of development complications. CONCLUSIONS We describe heliotrope rash as a risk factor for developing complications in our cohort of JDM patients, an easy-to-evaluate clinical sign that could help us to identify the group of patients we should monitor closely for this complication.
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Affiliation(s)
- Sonia Carriquí-Arenas
- Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
| | - Juan Manuel Mosquera
- Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Estefanía Quesada-Masachs
- Rheumatology Department, Pediatric Rheumatology Unit, Vall d'Hebron University Hospital, Barcelona Hospital Campus, Barcelona, Spain
| | - Mireia López
- Rheumatology Department, Pediatric Rheumatology Unit, Vall d'Hebron University Hospital, Barcelona Hospital Campus, Barcelona, Spain
| | - Daniel Clemente
- Pediatric Rheumatology Unit, Niño Jesús Hospital, Madrid, Spain
| | - Alina Boteanu
- Rheumatology Department, Ramón y Cajal University Hospital, Madrid, Spain
| | - Clara Udaondo
- Pediatric Rheumatology Unit, La Paz University Children's Hospital, CIBERINFEC (CIBER research network, Carlos III research institute), Madrid, Spain
| | - Jaime de Inocencio
- Pediatric Rheumatology Unit, University Hospital 12 de octubre, Madrid, Spain
- Pediatrics Complutense, University of Madrid, Madrid, Spain
| | - Juan Carlos Nieto
- Rheumatology Department, Gregorio Marañón General University Hospital, Madrid, Spain
| | - Leyre Riancho
- Rheumatology Department, Valdecilla Hospital, Santander, Spain
| | - Esmeralda Núñez
- Pediatric Rheumatology Unit, Pediatric Unit. Maternal and Child Hospital, Regional University Hospital of Malaga, Málaga, Spain
| | - Judith Sánchez-Manubens
- Pediatric Rheumatology Unit, Pediatric Department, Parc Taulí University Hospital, Sabadell, Spain
- Investigation and innovation Institute I3PT, University Autónoma, Barcelona, Spain
| | - María José Lirola
- Pediatric, Universtiy Hospital Macarena. IHP Group (Hispalense Institute of Pediatrics), Sevilla, Spain
| | - Rosa Roldán
- Pediatric Rheumatology Unit, Rheumatology Department, University Hospital Reina Sofía, Córdoba, Spain
| | - Marisol Camacho
- Pediatric Rheumatology Unit, Virgen del Rocío University Hospital, Sevilla, Spain
| | - Melania Martínez
- Rheumatology Department, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Marta Medrano
- Rheumatology Department, Miguel Servet University Hospital, Zaragoza, Spain
| | - Paula Alcañiz
- Pediatra. Pediatric Rheumatology Unit, Virgen de la Arrixaca University Clinical Hospital, Murcia, Spain
| | - Jordi Antón
- Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Universitat de Barcelona (UB), Barcelona, Spain
| | - Estíbaliz Iglesias
- Pediatric Rheumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
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Ożga J, Mężyk E, Kmiecik W, Wojciechowski W, Żuber Z. Magnetic resonance imaging of the musculoskeletal system in the diagnosis of rheumatic diseases in the pediatric population. Reumatologia 2024; 62:196-206. [PMID: 39055724 PMCID: PMC11267661 DOI: 10.5114/reum/190262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Magnetic resonance imaging (MRI) of the musculoskeletal system is an examination increasingly performed for suspected juvenile idiopathic arthritis, chronic nonbacterial osteomyelitis and juvenile idiopathic inflammatory myopathies, as well as other rheumatic diseases of developmental age. T1-, T2- and PD-weighted with or without fat suppression or short tau inversion recovery/turbo inversion recovery magnitude (STIR/TIRM) sequences and post-contrast sequences are evaluated to diagnose pathological changes in the synovial membrane, subchondral bone marrow and surrounding soft tissues. Magnetic resonance imaging allows detection of synovitis, tenosynovitis, bursitis, and enthesitis as well as bone marrow edema and soft tissue edema. Several pediatric-specific MRI scoring systems have been developed and validated to standardize and facilitate the assessment of the extent of the inflammatory process and disease activity in MRI. Early detection of inflammatory changes allows the inclusion of comprehensive pharmacotherapy giving the possibility of permanent remission and objective measurement of the effectiveness of treatment.
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Affiliation(s)
- Joanna Ożga
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Poland
- Clinical Department of Pediatrics and Rheumatology, St. Louis Regional Specialised Children's Hospital, Krakow, Poland
| | - Elżbieta Mężyk
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Poland
- Clinical Department of Pediatrics and Rheumatology, St. Louis Regional Specialised Children's Hospital, Krakow, Poland
| | - Wojciech Kmiecik
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Poland
- Clinical Department of Pediatrics and Rheumatology, St. Louis Regional Specialised Children's Hospital, Krakow, Poland
| | - Wadim Wojciechowski
- Clinical Department of Pediatrics and Rheumatology, St. Louis Regional Specialised Children's Hospital, Krakow, Poland
- Department of Radiology, Jagiellonian University Medical College, Krakow, Poland
| | - Zbigniew Żuber
- Department of Pediatrics, Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Poland
- Clinical Department of Pediatrics and Rheumatology, St. Louis Regional Specialised Children's Hospital, Krakow, Poland
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13
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Zhang Y, Zou Y, Tan W, Lv C. Value of radiomics-based automatic grading of muscle edema in polymyositis/dermatomyositis based on MRI fat-suppressed T2-weighted images. Acta Radiol 2024; 65:632-640. [PMID: 38591947 DOI: 10.1177/02841851241244507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
BACKGROUND The precise and objective assessment of thigh muscle edema is pivotal in diagnosing and monitoring the treatment of dermatomyositis (DM) and polymyositis (PM). PURPOSE Radiomic features are extracted from fat-suppressed (FS) T2-weighted (T2W) magnetic resonance imaging (MRI) of thigh muscles to enable automatic grading of muscle edema in cases of polymyositis and dermatomyositis. MATERIAL AND METHODS A total of 241 MR images were analyzed and classified into five levels using the Stramare criteria. The correlation between muscle edema grading and T2-mapping values was assessed using Spearman's correlation. The dataset was divided into a 7:3 ratio of training (168 samples) and testing (73 samples). Thigh muscle boundaries in FS T2W images were manually delineated with 3D-Slicer. Radiomics features were extracted using Python 3.7, applying Z-score normalization, Pearson correlation analysis, and recursive feature elimination for reduction. A Naive Bayes classifier was trained, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curves and comparing sensitivity and specificity with senior doctors. RESULTS A total of 1198 radiomics parameters were extracted and reduced to 18 features for Naive Bayes modeling. In the testing set, the model achieved an area under the ROC curve of 0.97, sensitivity of 0.85, specificity of 0.98, and accuracy of 0.91. The Naive Bayes classifier demonstrated grading performance comparable to senior doctors. A significant correlation (r = 0.82, P <0.05) was observed between Stramare edema grading and T2-mapping values. CONCLUSION The Naive Bayes model, utilizing radiomics features extracted from thigh FS T2W images, accurately assesses the severity of muscle edema in cases of PM/DM.
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Affiliation(s)
- Yumei Zhang
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Yuefen Zou
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Wenfeng Tan
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Chengyin Lv
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
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14
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Kim H. Updates on efficacy and safety janus kinase inhibitors in juvenile dermatomyositis. Expert Rev Clin Immunol 2024; 20:589-602. [PMID: 38299575 PMCID: PMC11189608 DOI: 10.1080/1744666x.2024.2312819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 01/29/2024] [Indexed: 02/02/2024]
Abstract
INTRODUCTION Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a chronic or polycyclic disease course on standard therapy so better treatments are needed. An interferon signature is well-established in key tissues of JDM. Janus kinase inhibitors (jakinibs), which can decrease IFN signaling, are therefore appealing as a targeted therapy. AREAS COVERED Herein is a review of the growing literature on JDM patients in jakinibs, including specifics of their jakinib exposure, summary of efficacy, disease features, and characteristics of patients treated, and safety parameters. EXPERT OPINION The vast majority of refractory JDM patients respond to jakinib therapy, though they have varied features, doses, and previous/concurrent medications, and data is largely retrospective. Jakinibs are an exciting and promising treatment in JDM. Evaluation with larger prospective controlled studies is needed to answer remaining questions about jakinibs in JDM regarding dosing, which JDM patients to treat with jakinibs, potential biomarkers to use, and how best to monitor safety risks in JDM.
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Affiliation(s)
- Hanna Kim
- National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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15
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Yamazaki S, Shimizu M, Yakabe A, Inage E, Jimbo K, Suzuki M, Miyaoka F, Kaneko S, Irabu H, Shimbo A, Ohtomo Y, Mori M, Morio T, Shimizu T. Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature. Immunol Med 2024; 47:110-117. [PMID: 38557269 DOI: 10.1080/25785826.2024.2336687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.
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Affiliation(s)
- Susumu Yamazaki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
- Department of Pediatrics and Adolescent Medicine, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Masaki Shimizu
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ayane Yakabe
- Department of Pediatrics and Adolescent Medicine, Juntendo University Nerima Hospital, Tokyo, Japan
| | - Eisuke Inage
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Keisuke Jimbo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Futaba Miyaoka
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shuya Kaneko
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hitoshi Irabu
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Asami Shimbo
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshiyuki Ohtomo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masaaki Mori
- Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Morio
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Yang L, Guan W, Liu H, Li Y, Gong Y, Lv Q, Zeng Q, Wei Q, Zhang X, Chen W, Chen C, Sun L. Juvenile dermatomyositis with central nervous system involvement: two case reports from a retrospective single-center cohort, with literature review. Front Pediatr 2024; 12:1409950. [PMID: 38873583 PMCID: PMC11169638 DOI: 10.3389/fped.2024.1409950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 05/20/2024] [Indexed: 06/15/2024] Open
Abstract
Background Juvenile dermatomyositis (JDM) is a systemic autoimmune disease primarily involving the muscles and skin; it can also affect the central nervous system (CNS). The relevant literature provides limited information regarding the characteristics of JDM with CNS involvement. Method We reviewed patients with JDM who were hospitalized at our center between January 2016 and August 2023, with a focus on those with CNS involvement. The aim was to provide detailed case reports on these patients, and to summarize the relevant literature about the characteristics of similar cases. Results Among 193 hospitalized patients with JDM, two (1.03%) had CNS involvement. Two patients, a 5.5-year-old girl and an 11-year-old boy, were admitted with severe proximal muscle weakness and seizures, and presented with active cutaneous vasculitis. Both were ultimately diagnosed with JDM, with CNS involvement. Both patients had confirmed presence of anti-NXP2 antibody through myositis-specific antibody analysis. Additionally, they all exhibited hyperferritinemia and thrombocytopenia. Salvage therapies like intravenous methylprednisolone (IVMP) pulse therapy and/or plasma exchange were administered successfully. At final follow-up, both patients had achieved complete clinical response and full neurological recovery. Our literature review identified nine similar case studies. CNS involvement usually occurred within the first 10 months of the disease course, and most of these patients had fatal outcomes, with a mortality rate of 66.6% (6/9). Including the two patients described herein, the median age for disease onset is 10.5 years (range 4-17 years), and the male: female ratio is 6:5. Seizures are the most common neurological symptom, accompanied by active cutaneous vasculitis. The brain biopsies showed two distinct pathological presentations: one was central nervous system vasculitis, and the other was cerebral macrophage activation syndrome. Conclusions CNS involvement is a rare but life-threatening JDM complication. Herein, our cases and the literature indicate that it typically occurs within the first 10 months of the disease course and manifests as seizures, often accompanied by active cutaneous vasculitis, with fatal outcomes. Timely implementation of salvage therapies, like IVMP pulse therapy and plasma exchange, may significantly impact patient outcomes.
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Affiliation(s)
- Ling Yang
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- Department of Rheumatology, Children’s Hospital of Fudan University at Xiamen (Xiamen Children’s Hospital), Fujian, China
- National Children’s Medical Center, Shanghai, China
| | - Wanzhen Guan
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Haimei Liu
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Yifan Li
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Yinv Gong
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Qianying Lv
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Qiaoqian Zeng
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Qijiao Wei
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Xiaomei Zhang
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
| | - Weiming Chen
- National Children’s Medical Center, Shanghai, China
- Pediatric Intensive Care Unit, Children’s Hospital of Fudan University, Shanghai, China
| | - Chao Chen
- National Children’s Medical Center, Shanghai, China
- Department of Otolaryngology, Children’s Hospital of Fudan University, Shanghai, China
| | - Li Sun
- Department of Rheumatology, Children’s Hospital of Fudan University, Shanghai, China
- National Children’s Medical Center, Shanghai, China
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Covert LT, Patel H, Osman A, Duncan L, Dvergsten J, Truskey GA. Effect of type I interferon on engineered pediatric skeletal muscle: a promising model for juvenile dermatomyositis. Rheumatology (Oxford) 2024; 63:209-217. [PMID: 37094222 PMCID: PMC10765138 DOI: 10.1093/rheumatology/kead186] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/24/2023] [Accepted: 04/14/2023] [Indexed: 04/26/2023] Open
Abstract
OBJECTIVE To investigate pathogenic mechanisms underlying JDM, we defined the effect of type I IFN, IFN-α and IFN-β, on pediatric skeletal muscle function and expression of myositis-related proteins using an in vitro engineered human skeletal muscle model (myobundle). METHODS Primary myoblasts were isolated from three healthy pediatric donors and used to create myobundles that mimic functioning skeletal muscle in structural architecture and physiologic function. Myobundles were exposed to 0, 5, 10 or 20 ng/ml IFN-α or IFN-β for 7 days and then functionally tested under electrical stimulation and analyzed immunohistochemically for structural and myositis-related proteins. Additionally, IFN-β-exposed myobundles were treated with Janus kinase inhibitors (JAKis) tofacitinib and baricitinib. These myobundles were also analyzed for contractile force and immunohistochemistry. RESULTS IFN-β, but not IFN-α, was associated with decreased contractile tetanus force and slowed twitch kinetics. These effects were reversed by tofacitinib and baricitinib. Type I IFN paradoxically reduced myobundle fatigue, which did not reverse after JAKi. Additionally, type I IFN correlated with MHC I upregulation, which normalized after JAKi treatment, but expression of myositis-specific autoantigens Mi-2, melanocyte differentiation-associated protein 5 and the endoplasmic reticulum stress marker GRP78 were variable and donor specific after type I IFN exposure. CONCLUSION IFN-α and IFN-β have distinct effects on pediatric skeletal muscle and these effects can partially be reversed by JAKi treatment. This is the first study illustrating effective use of a three-dimensional human skeletal muscle model to investigate JDM pathogenesis and test novel therapeutics.
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Affiliation(s)
- Lauren T Covert
- Department of Pediatrics, Duke University Health System, Durham, NC, USA
| | - Hailee Patel
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Alaa Osman
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Lavonia Duncan
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Jeffrey Dvergsten
- Department of Pediatrics, Duke University Health System, Durham, NC, USA
| | - George A Truskey
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
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18
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Chawla S, Charan A, Tanwar GS. Widespread rash, leg pain and increased muscle bulk. Arch Dis Child Educ Pract Ed 2023; 108:467-468. [PMID: 37875325 DOI: 10.1136/archdischild-2023-326135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/23/2023] [Indexed: 10/26/2023]
Affiliation(s)
- Siddhi Chawla
- Radiology, Sardar Patel Medical College, Bikaner, Rajasthan, India
| | - Aditya Charan
- Radiology, Sardar Patel Medical College, Bikaner, Rajasthan, India
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19
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Stawicki MK, Abramowicz P, Sokolowska G, Wołejszo S, Grant WB, Konstantynowicz J. Can vitamin D be an adjuvant therapy for juvenile rheumatic diseases? Rheumatol Int 2023; 43:1993-2009. [PMID: 37566255 PMCID: PMC10495493 DOI: 10.1007/s00296-023-05411-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023]
Abstract
Vitamin D, known for its essential role in calcium and bone homeostasis, has multiple effects beyond the skeleton, including regulation of immunity and modulation of autoimmune processes. Several reports have shown suboptimal serum 25 hydroxyvitamin D [25(OH)D] levels in people with different inflammatory and autoimmune rheumatic conditions, and an association between 25(OH)D levels, disease activity and outcomes. Although most available data pertain to adults, insights often are extended to children. Juvenile rheumatic diseases (JRDs) are a significant health problem during growth because of their complex pathogenesis, chronic nature, multisystemic involvement, and long-term consequences. So far, there is no definitive or clear evidence to confirm the preventive or therapeutic effect of vitamin D supplementation in JRDs, because results from randomized controlled trials (RCTs) have produced inconsistent outcomes. This review aims to explore and discuss the potential role of vitamin D in treating selected JRDs. Medline/PubMed, EMBASE, and Scopus were comprehensively searched in June 2023 for any study on vitamin D supplementary role in treating the most common JRDs. We used the following keywords: "vitamin D" combined with the terms "juvenile idiopathic arthritis", "juvenile systemic scleroderma", "juvenile systemic lupus erythematosus", "juvenile inflammatory myopathies", "Behcet disease", "periodic fever syndromes" and "juvenile rheumatic diseases". Observational studies have found that serum 25(OH)D concentrations are lower in juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile systemic scleroderma, Behcet disease and proinflammatory cytokine concentrations are higher. This suggests that vitamin D supplementation might be beneficial, however, current data are insufficient to confirm definitively the complementary role of vitamin D in the treatment of JRDs. Considering the high prevalence of vitamin D deficiency worldwide, children and adolescents should be encouraged to supplement vitamin D according to current recommendations. More interventional studies, especially well-designed RCTs, assessing the dose-response effect and adjuvant effect in specific diseases, are needed to determine the potential significance of vitamin D in JRDs treatment.
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Affiliation(s)
- Maciej K. Stawicki
- Department of Pediatrics, Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, University Children’s Clinical Hospital in Bialystok, Waszyngtona Street 17, 15274 Bialystok, Poland
| | - Paweł Abramowicz
- Department of Pediatrics, Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, University Children’s Clinical Hospital in Bialystok, Waszyngtona Street 17, 15274 Bialystok, Poland
| | | | - Sebastian Wołejszo
- Department of Pediatrics, Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, University Children’s Clinical Hospital in Bialystok, Waszyngtona Street 17, 15274 Bialystok, Poland
| | - William B. Grant
- Sunlight, Nutrition, and Health Research Center, San Francisco, CA USA
| | - Jerzy Konstantynowicz
- Department of Pediatrics, Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, University Children’s Clinical Hospital in Bialystok, Waszyngtona Street 17, 15274 Bialystok, Poland
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20
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Perfetto J, Yoo DA, Tamashiro CY, Perron MM, Vasquez-Canizares N, Wahezi DM. Impact of SARS-CoV-2 on the clinical presentation of juvenile idiopathic inflammatory myopathies. Pediatr Rheumatol Online J 2023; 21:82. [PMID: 37568191 PMCID: PMC10422741 DOI: 10.1186/s12969-023-00861-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/19/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Growing evidence suggests that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger idiopathic inflammatory myopathies (IIM). Few studies have described individual juvenile IIM (JIIM) cases following SARS-CoV-2 infection, and none explored its potential effects on JIIM clinical presentation. We aim to investigate the impact of SARS-CoV-2 on JIIM in patients diagnosed before and after the onset of the Coronavirus Disease 2019 (COVID-19) pandemic. METHODS Patients diagnosed with JIIM before age 19 at The Children's Hospital at Montefiore were included. Demographics, clinical and laboratory data, and evidence of SARS-CoV-2 exposure were collected retrospectively. Patients were grouped by pre-COVID-19 (before January 1, 2020) and post-COVID-19 (January 1, 2020, or later). Descriptive statistics were used to summarize each variable. Non-parametric testing was performed using Fischer's exact test and Mann-Whitney U test. RESULTS Fifty-one patients were included, 13 (25%) diagnosed in the post-COVID-19 era. Of these, 10 (77%) had onset of JIIM symptoms after January 1, 2020; 6 (60%) with known or suspected SARS-CoV-2 exposure. Though not statistically significant, post-pandemic patients tended to be older, female, and have non-specific cutaneous manifestations. Despite reported delays in care for other pediatric diagnoses during the pandemic, fewer post-pandemic patients had delays in JIIM diagnosis. CONCLUSIONS This is the first study to explore the effects of SARS-CoV-2 on JIIM clinical presentation. While our exploratory single-center study did not find significant differences in JIIM diagnosed pre- and post-pandemic, larger prospective multicenter studies are warranted to evaluate this association and to explore clinical variances over time.
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Affiliation(s)
- Jessica Perfetto
- Division of Rheumatology, The Children's Hospital at Montefiore, 3334 Bainbridge Avenue, Bronx, NY, 10467, USA.
| | - Donna A Yoo
- Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Megan M Perron
- Division of Rheumatology, Children's Hospital Colorado, Aurora, CO, USA
| | - Natalia Vasquez-Canizares
- Division of Rheumatology, The Children's Hospital at Montefiore, 3334 Bainbridge Avenue, Bronx, NY, 10467, USA
| | - Dawn M Wahezi
- Division of Rheumatology, The Children's Hospital at Montefiore, 3334 Bainbridge Avenue, Bronx, NY, 10467, USA
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21
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Kamiya M, Kimura N, Umezawa N, Hasegawa H, Yasuda S. Muscle fiber necroptosis in pathophysiology of idiopathic inflammatory myopathies and its potential as target of novel treatment strategy. Front Immunol 2023; 14:1191815. [PMID: 37483632 PMCID: PMC10361824 DOI: 10.3389/fimmu.2023.1191815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/22/2023] [Indexed: 07/25/2023] Open
Abstract
Idiopathic inflammatory myopathies (IIMs), which are a group of chronic and diverse inflammatory diseases, are primarily characterized by weakness in the proximal muscles that progressively leads to persistent disability. Current treatments of IIMs depend on nonspecific immunosuppressive agents (including glucocorticoids and immunosuppressants). However, these therapies sometimes fail to regulate muscle inflammation, and some patients suffer from infectious diseases and other adverse effects related to the treatment. Furthermore, even after inflammation has subsided, muscle weakness persists in a significant proportion of the patients. Therefore, the elucidation of pathophysiology of IIMs and development of a better therapeutic strategy that not only alleviates muscle inflammation but also improves muscle weakness without increment of opportunistic infection is awaited. Muscle fiber death, which has been formerly postulated as "necrosis", is a key histological feature of all subtypes of IIMs, however, its detailed mechanisms and contribution to the pathophysiology remained to be elucidated. Recent studies have revealed that muscle fibers of IIMs undergo necroptosis, a newly recognized form of regulated cell death, and promote muscle inflammation and dysfunction through releasing inflammatory mediators such as damage-associated molecular patterns (DAMPs). The research on murine model of polymyositis, a subtype of IIM, revealed that the inhibition of necroptosis or HMGB1, one of major DAMPs released from muscle fibers undergoing necroptosis, ameliorated muscle inflammation and recovered muscle weakness. Furthermore, not only the necroptosis-associated molecules but also PGAM5, a mitochondrial protein, and reactive oxygen species have been shown to be involved in muscle fiber necroptosis, indicating the multiple target candidates for the treatment of IIMs acting through necroptosis regulation. This article overviews the research on muscle injury mechanisms in IIMs focusing on the contribution of necroptosis in their pathophysiology and discusses the potential treatment strategy targeting muscle fiber necroptosis.
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22
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Papadopoulou C, Chew C, Wilkinson MGL, McCann L, Wedderburn LR. Juvenile idiopathic inflammatory myositis: an update on pathophysiology and clinical care. Nat Rev Rheumatol 2023; 19:343-362. [PMID: 37188756 PMCID: PMC10184643 DOI: 10.1038/s41584-023-00967-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2023] [Indexed: 05/17/2023]
Abstract
The childhood-onset or juvenile idiopathic inflammatory myopathies (JIIMs) are a heterogenous group of rare and serious autoimmune diseases of children and young people that predominantly affect the muscles and skin but can also involve other organs, including the lungs, gut, joints, heart and central nervous system. Different myositis-specific autoantibodies have been identified that are associated with different muscle biopsy features, as well as with different clinical characteristics, prognoses and treatment responses. Thus, myositis-specific autoantibodies can be used to subset JIIMs into sub-phenotypes; some of these sub-phenotypes parallel disease seen in adults, whereas others are distinct from adult-onset idiopathic inflammatory myopathies. Although treatments and management have much improved over the past decade, evidence is still lacking for many of the current treatments and few validated prognostic biomarkers are available with which to predict response to treatment, comorbidities (such as calcinosis) or outcome. Emerging data on the pathogenesis of the JIIMs are leading to proposals for new trials and tools for monitoring disease.
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Affiliation(s)
- Charalampia Papadopoulou
- Department of Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), London, UK
- Rare Diseases Theme NIHR Biomedical Research Centre at GOSH, London, UK
| | - Christine Chew
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Meredyth G Ll Wilkinson
- Rare Diseases Theme NIHR Biomedical Research Centre at GOSH, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, UK
- Infection Immunity and Inflammation Research and Teaching Department, UCL GOS Institute of Child Health, London, UK
| | - Liza McCann
- Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Lucy R Wedderburn
- Department of Paediatric Rheumatology, Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), London, UK.
- Rare Diseases Theme NIHR Biomedical Research Centre at GOSH, London, UK.
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, London, UK.
- Infection Immunity and Inflammation Research and Teaching Department, UCL GOS Institute of Child Health, London, UK.
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23
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Wilkinson MGL, Moulding D, McDonnell TCR, Orford M, Wincup C, Ting JYJ, Otto GW, Restuadi R, Kelberman D, Papadopoulou C, Castellano S, Eaton S, Deakin CT, Rosser EC, Wedderburn LR. Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis. Ann Rheum Dis 2023; 82:658-669. [PMID: 36564154 PMCID: PMC10176342 DOI: 10.1136/ard-2022-223469] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/01/2022] [Indexed: 12/25/2022]
Abstract
OBJECTIVES To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). METHODS RNA-sequencing was performed on CD4+, CD8+, CD14+ and CD19+ cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. RESULTS Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. CONCLUSIONS These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.
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Affiliation(s)
- Meredyth G Ll Wilkinson
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
| | - Dale Moulding
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
- Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Thomas C R McDonnell
- Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
| | - Michael Orford
- Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Chris Wincup
- Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
| | - Joanna Y J Ting
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Georg W Otto
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Restuadi Restuadi
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
| | - Daniel Kelberman
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
- Experimental and Personalised Medicine, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Charalampia Papadopoulou
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
- Rheumatology, Great Ormond Street Hospital NHS Trust, London, UK
| | - Sergi Castellano
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
- Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Simon Eaton
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
- Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Claire T Deakin
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
| | - Elizabeth C Rosser
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- Centre for Rheumatology Research, Division of Medicine, University College London, London, UK
| | - Lucy R Wedderburn
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
- Centre for Adolescent Rheumatology Versus Arthritis at UCL UCLH and GOSH, UCL, London, UK
- NIHR Biomedical Research Centre, Great Ormond Street Hospital, London, UK
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24
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Fujiwara M, Wakiguchi H, Okazaki F, Korenaga Y, Uchida M, Sato R, Omoto M, Kanda T, Hasegawa S. Magnetic resonance imaging and pathological findings of fasciitis in anti-PM/Scl antibody-positive juvenile myositis. Int J Rheum Dis 2023; 26:577-580. [PMID: 36504181 DOI: 10.1111/1756-185x.14519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 12/14/2022]
Affiliation(s)
- Mayu Fujiwara
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hiroyuki Wakiguchi
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Fumiko Okazaki
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yuno Korenaga
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masashi Uchida
- Division of Pediatrics, JCHO Tokuyama Central Hospital, Shunan, Japan
| | - Ryota Sato
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masatoshi Omoto
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takashi Kanda
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Shunji Hasegawa
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan
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25
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Varnier GC, Consolaro A, Cheng IL, Silva Riveiro A, Pilkington C, Ravelli A. Experience with the use of mycophenolate mofetil in juvenile idiopathic inflammatory myopathies. Rheumatology (Oxford) 2023; 62:SI163-SI169. [PMID: 35929784 DOI: 10.1093/rheumatology/keac404] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The objective of this study was to evaluate the efficacy and safety of MMF in juvenile idiopathic inflammatory myopathies (JIIMs). METHODS Patients diagnosed with JIIM and treated with MMF enrolled in the Juvenile Dermatomyositis Research Group (JDRG) in the UK or followed at the Giannina Gaslini Institute in Genoa, Italy, were included. The following information was collected retrospectively at MMF initiation, at 3, 6 and 12 months after treatment start, and at last follow-up visit: clinical manifestations, laboratory data, physicians' subjective assessment of disease activity, standardized outcome measures of muscle strength/endurance, cutaneous disease activity, physical function, global disease activity, cumulative damage, and ongoing treatment. RESULTS Of the 29 patients included, 23 had juvenile DM and 6 had overlap myositis. During administration of MMF, improvement in measures of muscle strength, skin disease activity, and overall disease activity was seen, with an increase in the frequency of normal scores for Manual Muscle Test-8 from 50.0% to 83.3%, Childhood Myositis Activity Score from 53.5% to 88.9%, muscle component of DAS from 55.2% to 84.2%, skin component of DAS from 31.0% to 42.1%, visual analogue scale for skin disease activity from 25.0% to 47.4%, and visual analogue scale for overall disease activity from 7.1% to 42.1%. The number of patients with inactive disease increased from 10.3% at baseline to 68.5% at last follow-up. CS dose was significantly reduced, from 0.3 to 0.1 mg/kg/day. No relevant side effects were reported. CONCLUSION Our experience suggests that MMF is a valuable therapeutic option for the management of JIIM.
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Affiliation(s)
- Giulia Camilla Varnier
- Università degli Studi di Genova, Genoa, Italy.,Paediatric Rheumatology, Royal Manchester Children's Hospital, Manchester, UK
| | - Alessandro Consolaro
- Università degli Studi di Genova, Genoa, Italy.,Clinica Pediatrica e Reumatologica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Iek Leng Cheng
- Paediatric Rheumatology, Great Ormond Street Hospital, London, UK
| | | | | | - Angelo Ravelli
- Università degli Studi di Genova, Genoa, Italy.,Clinica Pediatrica e Reumatologica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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26
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Clinical and autoantibody phenotypes of juvenile dermatomyositis. Reumatologia 2022; 60:281-291. [PMID: 36186835 PMCID: PMC9494788 DOI: 10.5114/reum.2022.119045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Juvenile dermatomyositis (JDM) is a heterogeneous autoimmune inflammatory myositis with symmetrical proximal muscle weakness and a characteristic rash. Juvenile dermatomyositis is characterized by variable presentation and phenotypes. Detection of myositis autoantibodies is useful in improving JDM diagnosis and predicting the prognosis. In this literature review based on case series we analyze clinical and autoantibody phenotypes of JDM in four patients who were hospitalized in one regional center in Ukraine during the last 3 years and three of them presented in the time of the COVID-19 pandemic. The reviewed literature showed the last updates for the JDM diagnosis and the role of myositis autoantibodies in the prediction of disease course, systemic involvement, and malignancy risk. The presence of anti-synthetase syndrome in all presented patients, mainly due to anti-PL-7 autoantibodies, encourages further study with more patients and with detection of other myositis-specific autoantibodies to identify or refute certain regional features.
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27
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Koker O, Aktay Ayaz N. Autoimmune and autoinflammatory diseases with mucocutaneous manifestations: A pediatric rheumatology perspective. Int J Dermatol 2022; 62:723-736. [PMID: 35843911 DOI: 10.1111/ijd.16352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/25/2022] [Accepted: 06/24/2022] [Indexed: 12/01/2022]
Abstract
The presence of mucocutaneous manifestations has clinical significance, as it may be a part of the initial presentation or activation stage of both autoimmune and autoinflammatory rheumatic diseases. The cutaneous signs may display a particular morphological and topographic distribution according to taxonomy, whereas heterogeneity is likely observed among the individuals. The review aims to cluster and systematically approach the mucocutaneous manifestations met in autoimmune and autoinflammatory rheumatic diseases of childhood. The search strategy involved a comprehensive inquiry on Web of Science, PubMed, MEDLINE, and Embase databases using relevant search terms such as "dermatologic, cutaneous, mucocutaneous, skin, rash" for each disease and category. The awareness of the distinctive mucocutaneous manifestations and their correlation with rheumatic diseases provides a convenient definition, well-timed control of the underlying condition, and prevention of cosmetic issues. In the management of rheumatic diseases, planning the pertinent differential diagnosis and determining the requirement of histopathological assessment are essential with a multidisciplinary approach to rheumatology, dermatology, and allergy-immunology specialties.
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Affiliation(s)
- Oya Koker
- Istanbul Faculty of Medicine, Department of Pediatric Rheumatology, Istanbul University, Istanbul, Turkey
| | - Nuray Aktay Ayaz
- Istanbul Faculty of Medicine, Department of Pediatric Rheumatology, Istanbul University, Istanbul, Turkey
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28
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Stingl C, Dvergsten JA, Eng SWM, Yeung RSM, Fritzler MJ, Mason T, Crowson C, Voora D, Reed AM. Gene Expression Profiles of Treatment Response and Non-Response in Children With Juvenile Dermatomyositis. ACR Open Rheumatol 2022; 4:671-681. [PMID: 35616642 PMCID: PMC9374052 DOI: 10.1002/acr2.11445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 01/26/2022] [Accepted: 02/01/2022] [Indexed: 12/26/2022] Open
Abstract
Objective The study objective was to identify differences in gene expression between treatment responders (TRs) and treatment non‐responders (TNRs) diagnosed with juvenile dermatomyositis (JDM). Methods Gene expression analyses were performed using whole blood messenger RNA sequencing in patients with JDM (n = 17) and healthy controls (HCs; n = 10). Four analyses were performed (A1‐4) comparing differential gene expression and pathways analysis exploiting the timing of sample acquisition and the treatments received to perform these comparative analyses. Analyses were done at diagnosis and follow‐up, which averaged 7 months later in the cohort. Results At diagnosis, the expression of 10 genes differed between TRs and TNRs. Hallmark and canonical pathway analysis revealed 11 and 60 pathways enriched in TRs and 3 and 21 pathways enriched in TNRs, respectively. Pathway enrichment at diagnosis in TRs was strongest in pathways involved in metabolism, complement activation, and cell signaling as mediated by IL‐8, p38/microtubule associated protein kinases (MAPK)/extracellular signal‐regulated kinases (ERK), Phosphatidylinositol 3 Kinase Gamma (PI3Kγ), and the B cell receptor. Follow‐up hallmark and canonical pathway analysis showed that 2 and 14 pathways were enriched in TRs, whereas 24 and 123 pathways were enriched in treatment TNRs, respectively. Prior treatment with glucocorticoids significantly altered expression of 13 genes in the analysis of subjects at diagnosis with JDM as compared with HCs. Conclusion Numerous genes and pathways differ between TRs and TNRs at diagnosis and follow‐up. Prior treatment with glucocorticoids prior to specimen acquisition had a small effect on the performed analyses.
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Affiliation(s)
| | | | - Simon W M Eng
- The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rae S M Yeung
- The Hospital for Sick Children, Toronto, Ontario, Canada
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29
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Ledenko T, Sorić Hosman I, Ćorić M, Gagro A. Case Report: Simultaneously Developed Amyopathic Dermatomyositis and Autoimmune Sclerosing Cholangitis - a Coincidence or a Shared Immunopathogenesis? Front Immunol 2022; 13:825799. [PMID: 35281002 PMCID: PMC8906471 DOI: 10.3389/fimmu.2022.825799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/03/2022] [Indexed: 11/23/2022] Open
Abstract
Inflammatory rheumatic diseases (IRD) and autoimmune liver diseases (AILD) share many similarities regarding epidemiology, genetics, immunology and therapeutic regimens, so it is not surprising that approximately 20% of patients with AILD are diagnosed with an IRD as well. Clinical features and biochemical hallmarks of IRD and AILD often intertwine and cross diagnostic criteria. Therefore, the real distinction of underlying disorders in a patient with these comorbidities may be challenging. The present report is the first report of simultaneously developed juvenile dermatomyositis (JDM) and autoimmune sclerosing cholangitis (ASC) with both entities fulfilling the latest guidelines for a definite diagnosis. Both of these diagnoses are difficult to definitely establish since ASC has a similar serologic profile as autoimmune hepatitis and liver histological analysis is frequently non-specific, whereas clinically amyopathic JDM diagnosis depends mostly on classical dermatological symptoms, while the rest of the diagnostic criteria, including the necessity for skin or muscle biopsy and the presence of myositis specific antibodies, are still not uniformed. In spite of these challenges, our patient clearly met European League Against Rheumatism/American College of Rheumatology classification criteria for CAJDM and The European Society for Pediatric Gastroenterology, Hepatology and Nutrition diagnostic criteria for ASC. Since elevated serum transaminases, the presence of serum antinuclear antibodies and hypergammaglobulinemia could be explained as a part of both JDM and ASC, the underlying pathophysiology remains debatable. Intriguingly, JDM and ASC share genetic predisposition including human leukocyte antigen allele DRB1*0301 and tumor necrosis factor α 308A allele. Furthermore, both humoral and cellular components of the adaptive immune system contribute to the pathogenesis of JDM and ASC. Moreover, recent findings indicate that the loss of the CD28 expression on T-cells plays a significant role in their pathogenesis along with the Th17 immune pathway. Despite these common features that suggest shared autoimmunity, AILD and autoimmune myositis are traditionally studied and managed independently. The lack of therapies that target the underlying cause results in a high rate of adverse events due to unspecific immunosuppressive therapy. Shared autoimmunity is an ideal area to develop new, targeted immunotherapy that would hopefully be beneficial for more than one disease.
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Affiliation(s)
- Tomislav Ledenko
- Department of Pediatrics, Zadar General Hospital, Zadar, Croatia
| | - Iva Sorić Hosman
- Department of Pediatrics, Zadar General Hospital, Zadar, Croatia
| | - Marijana Ćorić
- Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia.,School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Gagro
- School of Medicine, University of Zagreb, Zagreb, Croatia.,Division of Pulmonology, Allergology, Immunology and Rheumatology, Department of Pediatrics, Children's Hospital Zagreb, Zagreb, Croatia
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Wang YT, Zhang Y, Tang T, Luo C, Liu MY, Xu L, Wang L, Tang XM. Anti-nuclear matrix protein 2+ juvenile dermatomyositis with severe skin ulcer and infection: A case report and literature review. World J Clin Cases 2022; 10:3579-3586. [PMID: 35611208 PMCID: PMC9048553 DOI: 10.12998/wjcc.v10.i11.3579] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/07/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Juvenile dermatomyositis (JDM) is an idiopathic inflammatory myopathy that occurs in childhood. It is characterized by muscle weakness and a characteristic rash. Previous literature reports have rarely described JDM with severe skin ulcers and infections.
CASE SUMMARY Herein, we describe a case of a 2-year-old female patient who suffered from JDM, whose myositis-specific autoantibodies were positive for anti-nuclear matrix protein 2 antibody, with progressively worsening skin ulcers and severe infections. The patient was treated with glucocorticoids and various immunosuppressants. Nevertheless, further progression of the disease and the combination of primary disease and severe infection in the later period were fatal.
CONCLUSION In children, anti-nuclear matrix protein 2+ JDM combined with skin ulcers often indicates severe disease. In such cases, personalized treatment for the primary disease and infection prevention and control are essential.
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Affiliation(s)
- Ya-Ting Wang
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Yu Zhang
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Tao Tang
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Chong Luo
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Ming-Yue Liu
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Li Xu
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Li Wang
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Xue-Mei Tang
- Department of Rheumatology and Immunology; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders (Chongqing); China International Science and Technology Cooperation base of Child Development and Critical Disorders; Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
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Hinze C, Dressler F, Schara-Schmidt U, Haas JP. Juvenile Dermatomyositis. AKTUEL RHEUMATOL 2022. [DOI: 10.1055/a-1769-4299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
ZusammenfassungDie juvenile Dermatomyositis (JDM) ist die häufigste chronische
entzündliche Myopathie des Kindesalters. In dieser Übersicht
soll der aktuelle Kenntnisstand hinsichtlich der Diagnostik, Behandlung und
Überwachung der JDM dargestellt werden. So liegen häufig
myositis-spezifische Antikörper vor, die mit klinischen
Phänotypen und dem Verlauf der Erkrankung korrelieren. Typ I Interferone
spielen eine wichtige Rolle in der Pathogenese der Erkrankung.
Möglicherweise kann diese Beobachtung in der Zukunft zu gezielten
Therapien führen. Da langfristig schwerwiegende Komplikationen, wie
z. B. Kalzinosen oder Lipodystrophie, drohen, besonders bei auf Dauer
unzureichend kontrollierter Erkrankung, ist eine möglichst rasche und
effektive Behandlung anzustreben. Zu diesem Zweck sollte eine intensive
Remissionsinduktionstherapie, gefolgt von einer zielgerichteten Therapie
angestrebt werden. Verschiedene validierte Messinstrumente stehen zur
Verfügung, um den Verlauf der Erkrankung zu beurteilen. Die
Pro-KIND-Initiative der Gesellschaft für Kinder- und Jugendrheumatologie
hat Praxis- und Konsens-basiert in Deutschland sowohl eine diagnostische als
auch eine Treat-to-Target-Behandlungsstrategie entwickelt. Im Rahmen nationaler
und internationaler Kollaborationen soll sich die Behandlung der JDM in der
Zukunft weiter verbessern.
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Affiliation(s)
- Claas Hinze
- Klinik für Pädiatrische Rheumatologie und Immunologie,
Universitätsklinikum Münster, Münster,
Germany
| | - Frank Dressler
- Klinik für Pädiatrische Pneumologie, Allergologie und
Neonatologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Ulrike Schara-Schmidt
- Abteilung für Neuropädiatrie, Zentrum für
Neuromuskuläre Erkrankungen im Kindes- und Jugendalter,
Universitätsklinikum Essen, Essen, Germany
| | - Johannes-Peter Haas
- German Center for Rheumatology in Children and Adolescents, Deutsches
Zentrum für Kinder- und Jugendrheumatologie Garmisch-Partenkirchen,
Garmisch-Partenkirchen, Germany
- Center for treatment of pain in young people, Zentrum für
Schmerztherapie junger Menschen, Garmisch-Partenkirchen, Germany
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Yoshida S, Matsumoto H, Fujita Y, Yokose K, Temmoku J, Matsuoka N, Yashiro-Furuya M, Asano T, Sato S, Suzuki E, Yago T, Yaguchi T, Aita T, Kusano M, Yamamoto T, Watanabe H, Migita K. Anti-Mi-2 and anti-TIF1-γ Double-Positive Juvenile Dermatomyositis Treated under Diagnosis of Chronic Eczema: A Case Report. TOHOKU J EXP MED 2022; 256:303-308. [PMID: 35296571 DOI: 10.1620/tjem.2022.j006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Shuhei Yoshida
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Haruki Matsumoto
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Kohei Yokose
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Jumpei Temmoku
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | | | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Eiji Suzuki
- Department of Rheumatology, Ohta Nishinouchi General Hospital Foundation
| | - Toru Yago
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Takae Yaguchi
- Department of General Internal Medicine, Fukushima Medical University School of Medicine
| | - Tetsuro Aita
- Department of General Internal Medicine, Fukushima Medical University School of Medicine
| | - Misaki Kusano
- Department of Dermatology, Fukushima Medical University School of Medicine
| | - Toshiyuki Yamamoto
- Department of Dermatology, Fukushima Medical University School of Medicine
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University School of Medicine
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine
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Kobayashi I, Shimomura M, Ueki M, Takezaki S, Okura Y, Nawate M, Yamada M, Takahashi Y, Ariga T. Development of Graves' disease during drug-free remission of juvenile dermatomyositis. Mod Rheumatol Case Rep 2022; 6:55-58. [PMID: 34515780 DOI: 10.1093/mrcr/rxab006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/18/2021] [Accepted: 06/03/2021] [Indexed: 12/18/2022]
Abstract
We report a Japanese boy with Graves' disease (GD) which developed during drug-free remission of juvenile dermatomyositis (JDM). He had been diagnosed with JDM at the age of 6 years by typical skin rashes, muscle weakness, elevated serum transaminase levels, and typical findings of both magnetic resonance imaging and muscle biopsy. Although anti-melanoma differentiation antigen 5 autoantibody was positive, there was no complication of interstitial lung disease. He showed good response to methylprednisolone pulse therapy followed by oral prednisolone in combination with weekly methotrexate (MTX) and achieved drug-free remission after 3.5 years of treatment. Nevertheless, serum levels of soluble interleukin-2 receptor (sIL-2R) gradually elevated to 3185 U/ml despite no signs of relapse or malignancy. Hyperactivity and attention deficit was also noted. One year and 3 months after the cessation of MTX, he presented with abdominal pain, tachycardia, and apparent goitre. Laboratory tests showed elevated free triiodothyronine, undetectable thyroid stimulating hormone (TSH), and positive anti-TSH receptor antibodies. 99mTc scintigraphy showed high levels of thyroid uptake. He was diagnosed with GD and treated with 15 mg/day of thiamazole. Although transient drug eruption was observed, his thyroid functions are currently well-controlled on 5 mg/day of thiamazole. In conclusion, to our knowledge, this is the first report in English literature describing complication of GD with JDM. Unexpected elevation of sIL-2R could be a clue to the diagnosis of GD during the follow-up of JDM.
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Affiliation(s)
- Ichiro Kobayashi
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan
| | - Masaki Shimomura
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
| | - Masahiro Ueki
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan
| | - Shunichiro Takezaki
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan
| | - Yuka Okura
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
| | - Mitsuru Nawate
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
| | - Masafumi Yamada
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan
| | - Yutaka Takahashi
- Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
| | - Tadashi Ariga
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaidô, Japan
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Loarce-Martos J, Larena C, Blázquez MÁ, Joven BE, Carreira PE, Martínez-Barrio J, Monteagudo I, López-Longo FJ, Ruiz L, López-Robledillo JC, Almodóvar R, Llorente I, Tomero E, García-de la Peña P, Moruno H, Pérez A, Cobo-Ibáñez T, Lojo Oliveira L, Barbadillo MC, García-De Yébenes MJ, Nuño-Nuño L. Clinical Characteristics of Juvenile Idiopathic Inflammatory Myopathy and Comparison With Adult Patients: Analysis From a Multicentric Cohort in Spain. J Clin Rheumatol 2022; 28:e195-e202. [PMID: 33492027 DOI: 10.1097/rhu.0000000000001696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
METHODS This study reviewed the medical records of patients from the REMICAM cohort, a multicentric longitudinal study carried out in patients with IIM, followed up between 1980 and 2014 in 12 hospitals in Madrid, Spain. Patients with definite or probable JPM, JDM, adult DM, and adult PM according to the modified Bohan and Peter criteria were selected. We compared the characteristics between JDM and JPM, and between JIIM and adult IIM. RESULTS Eighty-six juvenile patients (75 JDMs and 11 JPMs) and 283 adult patients (133 DMs and 150 PMs) were included. Compared with patients with JDM, patients with JPM were older at diagnosis, had more fever and arthritis, and were less frequently treated with disease-modifying antirheumatic drugs (these differences were not statistically significant). Compared with patients with adult DM, those with JDM presented more frequently with calcinosis (33.8% vs 6.9%, p < 0.0001) and had less severe infections (4.3% vs 23.4%, p < 0.0001), malignancies (1.3% vs 25.6%, p < 0.0001), and mortality (3.5% vs 33%, p < 0.0001). Patients with JDM were treated less frequently with azathioprine (10.8% vs 44.7%, p < 0.0001). CONCLUSIONS Our findings confirm that JIIMs are a heterogeneous group of diseases with relevant differences compared with adult IIMs.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Ana Pérez
- Hospital Universitario Príncipe de Asturias
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Morphological Characteristics of Idiopathic Inflammatory Myopathies in Juvenile Patients. Cells 2021; 11:cells11010109. [PMID: 35011672 PMCID: PMC8750180 DOI: 10.3390/cells11010109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/25/2021] [Indexed: 12/16/2022] Open
Abstract
Background: In juvenile idiopathic inflammatory myopathies (IIMs), morphological characteristic features of distinct subgroups are not well defined. New treatment strategies require a precise diagnosis of the subgroups in IIM, and, therefore, knowledge about the pathomorphology of juvenile IIMs is warranted. Methods: Muscle biopsies from 15 patients (median age 8 (range 3–17) years, 73% female) with IIM and seven controls were analyzed by standard methods, immunohistochemistry, and transmission electron microscopy (TEM). Detailed clinical and laboratory data were accessed retrospectively. Results: Proximal muscle weakness and skin symptoms were the main clinical symptoms. Dermatomyositis (DM) was diagnosed in 9/15, antisynthetase syndrome (ASyS) in 4/15, and overlap myositis (OM) in 2/15. Analysis of skeletal muscle tissues showed inflammatory cells and diffuse upregulation of MHC class I in all subtypes. Morphological key findings were COX-deficient fibers as a striking pathology in DM and perimysial alkaline phosphatase positivity in anti-Jo-1-ASyS. Vascular staining of the type 1 IFN-surrogate marker, MxA, correlated with endothelial tubuloreticular inclusions in both groups. None of these specific morphological findings were present in anti-PL7-ASyS or OM patients. Conclusions: Morphological characteristics discriminate IIM subtypes in juvenile patients, emphasizing differences in aetiopathogenesis and supporting the notion of individual and targeted therapeutic strategies.
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Mrosak J, Banasiak K, Edelheit B, Lapin C, Tory H, Collins MS. Polymyxin-B Hemoperfusion as a Novel Treatment for Rapidly Progressive Interstitial Lung Disease in a Pediatric Patient Diagnosed With Anti-MDA5 Juvenile Dermatomyositis. J Clin Rheumatol 2021; 27:S480-S484. [PMID: 31743264 DOI: 10.1097/rhu.0000000000001191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sharma A, Bhattarai D, Gupta A, Guleria S, Rawat A, Vignesh P, Garg R, Singh S. Autoantibody Profile of Children with Juvenile Dermatomyositis. Indian J Pediatr 2021; 88:1170-1173. [PMID: 33694062 DOI: 10.1007/s12098-021-03680-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 01/24/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To study autoantibody profile in juvenile dermatomyositis (JDM) and to look for phenotypic associations of these autoantibodies, if any. METHODS Thirty-four children with JDM with a minimum follow-up duration of 24 mo were enrolled. Clinical findings and investigations at the time of diagnosis were noted from the clinic records. At inclusion, they were clinically evaluated for residual disease, disease activity and complications. All the enrolled patients were tested for antinuclear antibodies (ANA), muscle specific antibodies (MSA) and myositis associated autoantibodies (MAA). RESULTS ANA positivity was seen in 14/34 children. At least one MSA or MAA was present in 8/34 children. Anti-SRP, anti-MDA-5, and anti-Mi-2 antibodies were present in 4, 3, and 1 patient, respectively. Anti-SSA/Ro52 antibody was positive in 1 child. All four children with anti-SRP antibody were girls, who had polycyclic course. Two of them developed calcinosis. Prominent skin involvement with less severe muscle involvement and monocyclic course were seen in patients with anti-MDA-5 antibody. Two of them had arthritis/arthralgia at initial presentation. The only patient with anti-Mi-2 had normal muscle strength at enrollment. None of the patients had anti-synthetase antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ), anti-Ku, anti-Scl-70, anti-NXP-2 or anti-HMG CoA. CONCLUSION Eight patients tested positive for at least one MSA or MAA. The prevalence of autoantibodies was low. Positivity for anti-SRP, anti-MDA-5, anti-Mi-2 and anti-SSA/Ro52 antibodies was seen in 4, 3, 1 and 1 patients, respectively. Ethnic differences and testing for autoantibodies during/after therapy could be responsible for the low positivity rate for autoantibodies.
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Affiliation(s)
- Avinash Sharma
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Dharmagat Bhattarai
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Anju Gupta
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Sandesh Guleria
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pandiarajan Vignesh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ravinder Garg
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Surjit Singh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
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Prado-Checa I, Vet L, Navarro-Cubas X, Vet L. ECG of the Month. J Am Vet Med Assoc 2021; 259:479-481. [PMID: 34388013 DOI: 10.2460/javma.259.5.479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Abstract
PURPOSE OF REVIEW This review provides updates regarding the role of interferon (IFN) in juvenile dermatomyositis (JDM), including comparison to interferonopathies and therapeutic implications. RECENT FINDINGS Transcriptomic and protein-based studies in different tissues and peripheral IFN-α assessment have demonstrated the importance of the dysregulated IFN pathway in JDM. Additional studies have validated IFN-regulated gene and protein expression correlation with disease activity in blood and muscle, with potential to predict flares. Type I and II IFN both are dysregulated in peripheral blood and muscle, with more type I IFN in skin. Muscle studies connects hypoxia to IFN production and IFN to vascular dysfunction and muscle atrophy. JDM overlaps with interferonopathy phenotype and IFN signature. There are multiple case reports and case series noting decreased IFN markers and clinical improvement in refractory JDM with Janus kinase (JAK) inhibitors. SUMMARY Studies confirm IFN, particularly type I and II IFN, is an important part of JDM pathogenesis by the level of dysregulation and correlation with disease activity, as well as IFN recapitulating key JDM muscle pathology. Smaller studies indicate there may be differences by myositis-specific autoantibody group, but validation is needed. JAK inhibitors are a promising therapy as they can inhibit IFN signaling, but further study is needed regarding which patients will benefit, dosing, and safety monitoring.
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Affiliation(s)
- Hanna Kim
- Juvenile Myositis Pathogenesis and Therapeutics Unit, National Institute of Arthritis Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
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Orandi AB, Fotis L, Lai J, Morris H, White AJ, French AR, Baszis KW. Favorable outcomes with reduced steroid use in juvenile dermatomyositis. Pediatr Rheumatol Online J 2021; 19:127. [PMID: 34404425 PMCID: PMC8369654 DOI: 10.1186/s12969-021-00615-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/14/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND High-intensity glucocorticoid regimens are commonly used to induce and maintain remission in Juvenile Dermatomyositis but are associated with several adverse side-effects. Evidence-based treatment guidelines from North American and European pediatric rheumatology research societies both advocate induction with intravenous pulse steroids followed by high dose oral steroids (2 mg/kg/day), which are then tapered. This study reports the time to disease control with reduced glucocorticoid dosing. METHODS We retrospectively reviewed the records at a single tertiary-care children's hospital of patients diagnosed with Juvenile Dermatomyositis between 2000 and 2014 who had a minimum of 2 years of follow-up. The primary outcome measure was time to control of muscle and skin disease. Additional outcome measures included glucocorticoid dosing, effect of treatment on height, frequency of calcinosis, and complications from treatment. RESULTS Of the 69 patients followed during the study period, 31 fulfilled inclusion criteria. Median length of follow-up was 4.58 years, (IQR 3-7.5). Myositis control was achieved in a median of 7.1 months (IQR 0.9-63.4). Cutaneous disease control was achieved in a median of 16.7 months (IQR 4.3-89.5). The median starting dose of glucocorticoids was 0.85 mg/kg/day, (IQR 0.5-1.74). The median duration of steroid treatment was 9.1 months, (IQR 4.7-17.4), while the median duration of any pharmacotherapy was 29.2 months (IQR 10.4 to 121.3). Sustained disease control off medications was achieved in 21/31 (68%) patients by the end of review. Persistent calcinosis was identified in only one patient (3%). CONCLUSION Current accepted treatment paradigms for Juvenile Dermatomyositis include oral glucocorticoids beginning at 2 mg/kg/day and reduced over a prolonged time period. However, our results suggest that treatment using reduced doses and duration with early use of steroid-sparing agents is comparably effective in achieving favorable outcomes in Juvenile Dermatomyositis.
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Affiliation(s)
- Amir B. Orandi
- grid.4367.60000 0001 2355 7002Division of Pediatric Rheumatology/Immunology, Washington University of School of Medicine, St Louis, MO USA ,grid.66875.3a0000 0004 0459 167XPresent Address: Department of Pediatric and Adolescent Medicine, Division of Pediatric Rheumatology, Mayo Clinic, Rochester, MN USA
| | - Lampros Fotis
- grid.4367.60000 0001 2355 7002Division of Pediatric Rheumatology/Immunology, Washington University of School of Medicine, St Louis, MO USA ,grid.5216.00000 0001 2155 0800Present Address: Department of Pediatrics, Division of Pediatric Rheumatology, National and Kapodistrian University of Athens, Athens, Greece
| | - Jamie Lai
- grid.4367.60000 0001 2355 7002Department of Pediatrics, Washington University School of Medicine, St. Louis, MO USA ,grid.39382.330000 0001 2160 926XPresent Address: Department of Pediatrics, Division of Pediatric Rheumatology, Baylor College of Medicine, Houston, TX USA
| | - Hallie Morris
- grid.4367.60000 0001 2355 7002Department of Pediatrics, Washington University School of Medicine, St. Louis, MO USA ,grid.253615.60000 0004 1936 9510Present Address: Division of Neonatology, George Washington University School of Medicine and Health Science, Washington, D.C, USA
| | - Andrew J. White
- grid.4367.60000 0001 2355 7002Division of Pediatric Rheumatology/Immunology, Washington University of School of Medicine, St Louis, MO USA
| | - Anthony R. French
- grid.4367.60000 0001 2355 7002Division of Pediatric Rheumatology/Immunology, Washington University of School of Medicine, St Louis, MO USA
| | - Kevin W. Baszis
- grid.4367.60000 0001 2355 7002Division of Pediatric Rheumatology/Immunology, Washington University of School of Medicine, St Louis, MO USA
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Benvenuto S, Gortani G, Bussani R, Poropat F, Murru FM, Carrozzi M, Tommasini A, Taddio A. Severe onset of inflammatory myositis in a child: think to paraneoplastic myositis. Ital J Pediatr 2021; 47:146. [PMID: 34210321 PMCID: PMC8252287 DOI: 10.1186/s13052-021-01098-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 06/01/2021] [Indexed: 11/17/2022] Open
Abstract
Background Juvenile idiopathic inflammatory myopathies (JIIMs) are a group of heterogenous, acquired, autoimmune disorders that affect the muscle. While the association between IIMs and malignancy has been widely reported in adults, cancer-associated myositis (CAM) is rare in children, so that routine malignancy screening is not generally performed. This report shows a case of severe CAM in a child. Case presentation An 11-years-old girl presented with worsening dyspnea after a 3-weeks history of progressive proximal weakness, myalgia, dysphagia, and weight loss. Her past history was remarkable for a type I Arnold-Chiari malformation associated with an anterior sacral meningocele. Physical examination showed severe hypotony and hypotrophy. Pulse oximetry and blood test showed a type II respiratory failure (SpO2 88%, pCO2 68 mmHg) and increased muscle enzyme levels (CPK 8479 U/L, AST 715 U/L, ALT 383 U/L, LDH 1795 U/L). The patient needed invasive mechanical ventilation. Inflammatory myositis was considered and treatment with intravenous methylprednisolone (30 mg/Kg/day for 3 days followed by 2 mg/Kg/day) and IVIG (1 g/kg/day for 2 days) was started. Muscle biopsy showed endomysial and perimysial necrosis and inflammation. The presence of serum anti-TIF1-γ antibody positivity led to a malignancy screening. Whole-body MRI showed a mature teratoma underneath sacral meningocele and both lesions were surgically removed. Given the histological and clinical severity of the myopathy, mycophenolate (500 mg twice a day) and rituximab (360 mg/m2, 4 weekly infusions) were added. Due to extreme muscular wasting, severe malnutrition and intolerance to enteral feeding the patient needed a transient tracheostomy and parenteral nutrition, followed by physiotherapy, speech therapy and nocturnal non-invasive ventilation. A complete remission was achieved 3 months after. Conclusions Among cancer-associated autoantibodies (CAAs) in adult patients, anti-TIF1-γ carries the highest risk of CAM, which recognizes with a high likelihood a paraneoplastic pathogenesis. In children, anti-TIF1-γ antibody has been associated with severe cutaneous disease, lipodystrophy, and chronic disease course, but not with CAM, which is overall rare in younger patients. Severe onset of a JIIM, especially if anti-TIF1-γ antibody positive, should prompt suspect of a CAM and lead to a screening for malignancy.
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Affiliation(s)
| | - Giulia Gortani
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | | | - Federico Poropat
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Flora Maria Murru
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Marco Carrozzi
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Alberto Tommasini
- University of Trieste, Via dell'Istria 65/1, Trieste, Italy.,Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
| | - Andrea Taddio
- University of Trieste, Via dell'Istria 65/1, Trieste, Italy.,Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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Dvergsten JA, Reed AM, Landerman L, Pisetsky DS, Ilkayeva O, Huffman KM. Metabolomics Analysis Identifies a Lipidomic Profile in Treatment Naïve Juvenile Dermatomyositis Patients versus Healthy Control Subjects. Rheumatology (Oxford) 2021; 61:1699-1708. [PMID: 34185053 PMCID: PMC8996785 DOI: 10.1093/rheumatology/keab520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 06/16/2021] [Indexed: 12/17/2022] Open
Abstract
Objectives To perform an exploratory study to identify a JDM serum metabolic profile that differs from healthy controls (HCs) and responds to immunosuppressive treatment. Methods Blood was collected from 9 HCs and 10 patients diagnosed with probable (n = 4) or definite (n = 6) JDM based on the criteria of Bohan and Peter for myositis, with 7 of the 10 providing longitudinal samples following initiation of treatment; these patients comprised the treatment-naïve cohort. Sera underwent mass spectroscopy–based measurements of targeted metabolic intermediates, including 15 amino acids, 45 acylcarnitines (ACs), 15 ceramides and 29 sphingomyelins. Principal components analysis reduced metabolites into smaller sets of factors each comprised of correlated metabolic intermediates. Factor scores and metabolite concentrations were compared with HCs using two-sample t-tests while treatment effects were evaluated using paired t-tests. Results Of eight principal components analysis–derived metabolite factors (one AC, two amino acids, three sphingosine and two ceramide), two were significantly associated with JDM: one AC factor containing mostly long-chain ACs (P = 0.049) and one ceramide factor (P < 0.01). For 12 individual ACs, mostly long chain, and three ceramides, concentrations were significantly greater for JDM than HCs. Factors based on these individual metabolites showed decreasing scores with treatment (P = 0.03 and P < 0.01, respectively). Conclusion While additional validation is needed, these lipids have potential as JDM serum diagnostic and/or treatment biomarkers. Additionally, the significant association of long-chain ACs and ceramides with JDM offers insights regarding pathogenesis, implicating dysregulation of mitochondrial fatty acid β-oxidation.
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Affiliation(s)
- Jeffrey A Dvergsten
- Department of Pediatrics, Duke Children's Hospital, Duke University Medical Center, Durham, NC, USA
| | - Ann M Reed
- Department of Pediatrics, Duke Children's Hospital, Duke University Medical Center, Durham, NC, USA
| | - Lawrence Landerman
- Department of Pediatrics, Duke Children's Hospital, Duke University Medical Center, Durham, NC, USA
| | - David S Pisetsky
- Department of Medicine and Immunology, Duke University Medical Center and Research Service, Durham VA Medical Center, Durham, NC, USA
| | - Olga Ilkayeva
- Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA
| | - Kim M Huffman
- Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA
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Perron MM, Vasquez-Canizares N, Tarshish G, Wahezi DM. Myositis autoantibodies in a racially diverse population of children with idiopathic inflammatory myopathies. Pediatr Rheumatol Online J 2021; 19:92. [PMID: 34118936 PMCID: PMC8199392 DOI: 10.1186/s12969-021-00574-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 05/20/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Juvenile idiopathic inflammatory myopathies (JIIMs) is a group of autoimmune disorders, including juvenile dermatomyositis (JDM), juvenile polymyositis (JPM) and overlap myositis, that are characterized by proximal muscle weakness, elevated levels of serum muscle enzymes, and pathognomonic skin findings. While the exact etiology of JIIMs is unclear, the presence of myositis specific autoantibodies (MSAs) have been associated with certain clinical phenotypes, organ involvement and disease prognosis. To date, there have been few studies of the associations between MSA presence and patient ethnicity. It is important to understand the extent to which ethnicity impacts disease manifestations, organ involvement and clinical outcomes. The goal of our study is to determine MSA and myositis associated autoantibody (MAA) presence, clinical phenotype, and disease course in a racially diverse population of pediatric patients with JIIMs. METHODS Patients age 2-21 years with a prior diagnosis of JDM, JPM or overlap myositis, who had been tested for MSA/MAA, were eligible for study inclusion. Clinical and laboratory data were collected retrospectively via manual chart review in this single-center study. Descriptive statistics were performed to summarize each variable. Given the small sample size, non-parametric testing was performed using Fischer's exact test, Wilcoxon rank sum test and Kruskal-Wallis test. RESULTS Thirty one patients were included in the analysis. Race and ethnicity were self-reported as Hispanic (48.4%), white (25.8%), and Black (25.8%). The most prevalent MSAs were anti-MDA5 (25.8%), anti-p155/140 (22.6%) and anti-MJ (19.4%). Presence of autoantibodies (p = 0.04) and pulmonary disease (p = 0.03) were significantly higher in patients of Black or Hispanic descent compared with white descent. Anti-MDA5 antibodies, cutaneous ulceration, cardiopulmonary involvement, hospitalizations and one death were only reported in patients with Black or Hispanic descent. Patients with anti-MDA5 antibodies were more likely to be male (p = 0.04) and to have cutaneous ulceration (p = 0.02). CONCLUSIONS This study describes the prevalence of MSA/MAA in a racially diverse group of patients with JIIM and further delineates clinical phenotype and disease complications in these groups. We found a relatively high proportion of children with anti-MDA5 antibodies and described potentially worse clinical courses in children of Black or Hispanic descent. Further investigation is warranted to examine these findings.
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Affiliation(s)
- Megan Mariko Perron
- Children's Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY, 10467, USA. .,Children's Hospital Colorado, 13123 East 16th Avenue, Aurora, CO, 80045, USA.
| | - Natalia Vasquez-Canizares
- grid.414114.50000 0004 0566 7955Children’s Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467 USA
| | - Gabriel Tarshish
- grid.414114.50000 0004 0566 7955Children’s Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467 USA
| | - Dawn M. Wahezi
- grid.414114.50000 0004 0566 7955Children’s Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467 USA
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Ran J, Yin C, Liu C, Li Y, Hou B, Morelli JN, Dai B, Li X. The Diagnostic Value of MR IVIM and T2 Mapping in Differentiating Autoimmune Myositis From Muscular Dystrophy. Acad Radiol 2021; 28:e182-e188. [PMID: 32417032 DOI: 10.1016/j.acra.2020.04.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/11/2020] [Accepted: 04/12/2020] [Indexed: 01/15/2023]
Abstract
RATIONALE AND OBJECTIVES To confirm the feasibility and compare the accuracy of magnetic resonance imaging intravoxel incoherent motion (IVIM) and T2 mapping models for the differentiation of autoimmune myositis from muscular dystrophy. MATERIALS AND METHODS Fourty-two autoimmune myositis and 11 muscular dystrophy patients proven by diagnostic criteria were enrolled in the study. Conventional MR sequences, IVIM, and T2 mapping through the bilateral thighs were obtained as well as blood samples for all patients. IVIM and T2 mapping parameters as well as serum markers were compared between the autoimmune myositis and muscular dystrophy groups. Mann-Whitney U tests were performed for statistical analysis along with receiver operating characteristic curves. Spearman correlation coefficient models were constructed to analyze the correlation between IVIM and T2 mapping with serological parameters. RESULTS The intramuscular apparent diffusion coefficient, tissue diffusivity (D), perfusion fraction (fp), and T2 relaxation time values were statistically significantly different between the autoimmune myositis and muscular dystrophy groups (p < 0.05). Pseudo diffusivity (Dp) values showed no statistical difference between the groups (p > 0.05). D parameter of IVIM sequences differentiated autoimmune and muscular dystrophy with a higher specificity of 75.60%. T2 values within the thighs were correlated with serum creatine kinase and lactate dehydrogenase levels (p < 0.05). CONCLUSION Thigh muscle IVIM and T2 mapping parameters are useful in differentiating autoimmune myositis from muscular dystrophy, particularly the IVIM parameters.
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Affiliation(s)
- Jun Ran
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Cuilin Yin
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Chanyuan Liu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Yitong Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - Bowen Hou
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China
| | - John N Morelli
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bin Dai
- Department of General Surgery, General Hospital of the Central Theater Command of the People's Liberation Army, Wuhan, People's Republic of China
| | - Xiaoming Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Road, Wuhan 430030, Hubei Province, People's Republic of China.
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Hou C, Durrleman C, Periou B, Barnerias C, Bodemer C, Desguerre I, Quartier P, Melki I, Rice GI, Rodero MP, Charuel JL, Relaix F, Bader-Meunier B, Authier F, Gitiaux C. From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies. Arthritis Rheumatol 2021; 73:1044-1052. [PMID: 33314705 DOI: 10.1002/art.41625] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 11/24/2020] [Accepted: 12/10/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology. METHODS The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed. RESULTS ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing. CONCLUSION Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.
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Affiliation(s)
- Cyrielle Hou
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Paris, France
| | - Chloé Durrleman
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Centre de Reference pour les Maladies Neuromusculaires, FILNEMUS, Paris, France
| | - Baptiste Periou
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Hôpital Henri-Mondor, AP-HP, Paris, France
| | - Christine Barnerias
- Centre de Reference pour les Maladies Neuromusculaires, FILNEMUS, Paris, France
| | | | - Isabelle Desguerre
- Centre de Reference pour les Maladies Neuromusculaires, FILNEMUS, Paris, France
| | | | - Isabelle Melki
- Laboratoire de Neurogénétique et Neuroinflammation, Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Gillian I Rice
- University of Manchester School of Biological Sciences, Manchester, UK
| | - Mathieu P Rodero
- Laboratoire de Chimie et Biologie, Modélisation et Immunologie pour la Thérapie, CNRS UMR 8601, Université Paris-Descartes, Paris, France
| | | | - Fréderic Relaix
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Paris, France
| | | | - FrançoisJérôme Authier
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Centre de Reference pour les Maladies Neuromusculaires, Hôpital Henri-Mondor, AP-HP, FILNEMUS, Paris, France
| | - Cyril Gitiaux
- Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Centre de Reference pour les Maladies Neuromusculaires, Hôpital Necker-Enfants Malades, AP-HP, FILNEMUS, Paris, France
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Kishi T, Warren-Hicks W, Bayat N, Targoff IN, Huber AM, Ward MM, Rider LG. Corticosteroid discontinuation, complete clinical response and remission in juvenile dermatomyositis. Rheumatology (Oxford) 2021; 60:2134-2145. [PMID: 33067611 DOI: 10.1093/rheumatology/keaa371] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/31/2020] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE A North American registry of JDM patients was examined for frequency of and factors associated with corticosteroid discontinuation, complete clinical response and remission. METHODS We evaluated probability of achieving final corticosteroid discontinuation, complete clinical response and remission in 307 JDM patients by Weibull time-to-event modelling; conditional probability of complete clinical response and remission using Bayesian network modelling; and significant predictors with multivariable Markov chain Monte-Carlo Weibull extension models. RESULTS The probability of corticosteroid discontinuation was 56%, complete clinical response 38% and remission 30% by 60 months after initial treatment in 105 patients. The probability of remission was conditional on corticosteroid discontinuation and complete clinical response. Photosensitivity, contractures and a longer time to complete clinical response were predictive of the time to final corticosteroid discontinuation. Anti-MJ (NXP2) autoantibodies and a Northwest residential geoclimatic zone were predictive of shorter time to complete clinical response, while dysphonia, contractures, an increase in medications within 24 months and a longer time to corticosteroid discontinuation were associated with longer time to complete clinical response. Anti-p155/140 (TIF1) autoantibodies, an increase in medications within 12-24 months, or longer times to corticosteroid discontinuation and complete clinical response were associated with longer time to remission. CONCLUSION JDM patients achieve favourable outcomes, including corticosteroid discontinuation, complete clinical response and remission, although timelines for these may be several years based on time-dependent analyses. These outcomes are inter-related and strong predictors of each other. Selected clinical features and myositis autoantibodies are additionally associated with these outcomes.
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Affiliation(s)
- Takayuki Kishi
- Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD
| | | | - Nastaran Bayat
- Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD
| | - Ira N Targoff
- VA Medical Center, University of Oklahoma Health Sciences Center.,Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Adam M Huber
- IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Michael M Ward
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lisa G Rider
- Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD
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Yamazaki K, Ohta A, Akioka S, Yamasaki Y, Ohara A, Nakaseko H, Nishimura K, Kobayashi N, Nishida Y, Sato S, Takezaki S, Kishi T, Hashimoto M, Kobayashi I, Mori M. External validation of the EULAR/ACR idiopathic inflammatory myopathies classification criteria with a Japanese paediatric cohort. Rheumatology (Oxford) 2021; 60:802-808. [PMID: 32810274 DOI: 10.1093/rheumatology/keaa274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/03/2020] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria to classify juvenile IIMs (JIIMs) in an Asian paediatric population. METHODS Sixty-eight JIIM patients and 49 non-JIIM patients diagnosed at seven major paediatric rheumatology centres in Japan between 2008 and 2015 were enrolled. Retrospective data were collected, and each patient's data form was submitted. The expert group reviewed the forms and re-examined the diagnoses. The EULAR/ACR criteria were then applied and the probability of having JIIM was determined for each case. The sensitivity and specificity of the EULAR/ACR criteria were compared with those of other existing criteria. RESULTS The sensitivity/specificity of the EULAR/ACR classification criteria were 92.1/100% with muscle biopsy data (n = 38); 86.7/100% without muscle biopsy data (n = 30) and 89.7/100% in our total cohort (n = 68). The sensitivity of Bohan and Peter's criteria and Tanimoto's criteria were 80.9 and 64.7% in our total cohort, respectively. Among 68 physician-diagnosed JIIM patients, seven cases (three JDM and four overlap myositis) were not classified as JIIM because the probability did not reach the cut-off point (55%). The three JDM patients all presented with only one of the three skin manifestations that are listed in the criteria: Gottron's sign. CONCLUSION Our validation study with Japanese JIIM cases indicates that the EULAR/ACR classification criteria for IIM generally perform better than existing diagnostic criteria for myositis.
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Affiliation(s)
- Kazuko Yamazaki
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Akiko Ohta
- Division of Public Health, Department of Social Medicine, Faculty of Medicine, Saitama Medical University, Moroyama, Japan
| | - Shinji Akioka
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuichi Yamasaki
- Department of Pediatrics, Kagoshima University Hospitals, Kagoshima, Japan
| | - Asami Ohara
- Department of Infection and Immunology, Aichi Children's Health and Medical Center, Obu, Japan
| | - Haruna Nakaseko
- Department of Infection and Immunology, Aichi Children's Health and Medical Center, Obu, Japan
| | - Kenichi Nishimura
- Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Yutaka Nishida
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Sato
- Department of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan
| | - Shunichiro Takezaki
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takayuki Kishi
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Motomu Hashimoto
- Department of Advanced Medicine for Rheumatic Diseases, Kyoto University, Kyoto, Japan
| | - Ichiro Kobayashi
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masaaki Mori
- Department of Lifetime Clinical Immunology, Tokyo Medical and Dental University, Tokyo, Japan
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Wang K, Zhang Z, Meng D, Li J. Investigating genetic drivers of juvenile dermatomyositis pathogenesis using bioinformatics methods. J Dermatol 2021; 48:1007-1020. [PMID: 33891717 DOI: 10.1111/1346-8138.15856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 11/30/2022]
Abstract
Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. The pathogenic mechanisms remain ill-defined. The purpose of this study was to identify key genes related to JDM. Microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEG) were identified. Then, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and protein-protein interaction (PPI) network were carried out. In addition, the hub genes were selected by cytoHubba. The expression profile and diagnostic capacity (receiver-operator curve [ROC]) of interested hub genes were verified. Gene set enrichment analysis (GSEA) was also carried out. Moreover, the signature of hub genes was then used as a search query to explore the Connectivity Map (CMAP). A total of 128 DEG were identified. The enriched functions and pathways of the DEG include response to virus, negative regulation of cell migration, cadmium ion transmembrane transport, defense response to Gram-negative bacterium, positive regulation of megakaryocyte differentiation, and negative regulation of angiogenesis. Twenty-one hub genes were identified. The expression levels of the interested genes were also confirmed. ROC analysis confirmed that the expression of these genes can distinguish JDM from controls. GSEA showed that these genes are mainly related to "inflammatory response", "complement", "interferon-α response", "IL6/JAK/STAT3 signaling", "TGF-β signaling", "IL2/STAT5 signaling" and "TNF-α signaling via NF-κB". The CMAP research found some compounds with the potential to counteract the effects of the dysregulated molecular signature in JDM. In this study, bioinformatics methods were used to identify DEG, which helps us understand the molecular mechanisms of JDM and provide candidate targets for diagnosis and treatment of JDM.
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Affiliation(s)
- Kai Wang
- Department of Rheumatology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Zhongyuan Zhang
- Department of Rheumatology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Deqian Meng
- Department of Rheumatology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Ju Li
- Department of Rheumatology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, China
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Okiyama N. Clinical Features and Cutaneous Manifestations of Juvenile and Adult Patients of Dermatomyositis Associated with Myositis-Specific Autoantibodies. J Clin Med 2021; 10:jcm10081725. [PMID: 33923564 PMCID: PMC8073628 DOI: 10.3390/jcm10081725] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 11/16/2022] Open
Abstract
Dermatomyositis is one of the idiopathic inflammatory myopathies, which is characterized with specific skin manifestations, and considered as an autoimmune disease. Dermatomyositis is a heterogeneous disorder with various presences, severities and characteristics of myositis, dermatitis, and interstitial lung disease. Our and others' data showed that myositis-specific autoantibodies have been associated with distinct clinical features. This article reviewed the epidemiology and characteristic clinical features of the different types of antibody-associated dermatomyositis in adult and juvenile patients, which include the severity of myopathy, the potential complication of interstitial lung disease, potential association with malignancies, and characteristic cutaneous manifestations.
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Affiliation(s)
- Naoko Okiyama
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
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Zheng Q, Zhu K, Gao CN, Xu YP, Lu MP. Prevalence of Epstein-Barr virus infection and characteristics of lymphocyte subsets in newly onset juvenile dermatomyositis. World J Pediatr 2021; 17:205-209. [PMID: 31549298 DOI: 10.1007/s12519-019-00314-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 09/02/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND The underlying etiology of juvenile dermatomyositis (JDM) is unknown. T cell deficiency as well as Epstein-Barr virus (EBV) infection had been suspected to be involved in the pathogenesis, but it has been poorly evaluated in JDM patients. METHODS This study described the traits of T and B lymphocyte subsets in newly onset JDM patients and the incidence of EBV infection in JDM patients compared with match controls. Newly developed JDM patients from 2014 to 2018 were included in the study. Lymphocytes with different markers (CD3+, CD3+CD4+, CD3+CD8+, CD3-CD19+ and CD3-CD16+CD56+) were tested with flow cytometry in the first admission or after 6 months of treatment. Statistical analysis was conducted to compare the EBV infection in the group of JDM patients and controls. RESULTS We observed that JDM patients had higher positive rate of Epstein-Barr nuclear antigen-immunoglobulin G (IgG) (P < 0.0001) as well as EBV capsid antigen-IgG (P < 0.05) than normal controls. CD3-CD16+CD56+ lymphocyte was found to be extremely low in early stage of JDM patients, but increased after 6 months of treatment (P = 0.0091). CONCLUSIONS The level of CD3-CD16+CD56+ cells may associate with the clinical course of JDM. EBV may act as an environmental factor predisposing patients to the development of JDM.
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Affiliation(s)
- Qi Zheng
- Department of Rheumatology, Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, 57# Zhu Gan Road, Hangzhou, 310000, China
| | - Kun Zhu
- Department of Pathology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cai-Na Gao
- Department of Rheumatology, Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, 57# Zhu Gan Road, Hangzhou, 310000, China
| | - Yi-Ping Xu
- Department of Rheumatology, Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, 57# Zhu Gan Road, Hangzhou, 310000, China
| | - Mei-Ping Lu
- Department of Rheumatology, Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine, 57# Zhu Gan Road, Hangzhou, 310000, China.
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