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Current Opinion in Pulmonary Medicine Sep 2023In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and... (Review)
Review
PURPOSE OF REVIEW
In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and myositis-associated (MSA and MAA) antibodies, can predict the clinical phenotype and progression over time. This review will focus on the characteristics and management of antisynthetase syndrome related ILD and anti-MDA5 positive ILD, which are the most clinically relevant subtypes.
RECENT FINDINGS
The prevalence of ILD in IIM has been estimated in Asia, North America and Europe at 50, 23 and 26%, respectively, and is increasing. In antisynthetase syndrome related ILD, the clinical presentation, progression and prognosis varies among anti-ARS antibodies. ILD is more common and severe in patients with anti-PL-7/anti-PL-12 antibodies when compared with anti Jo-1 patients. The prevalence of anti-MDA5 antibodies is higher in Asians (11-60%) than in whites (7-16%). Sixty-six percent of antisynthetase syndrome patients had 'chronic ILD' compared with the more rapidly progressive ILD (RP-ILD) seen in 69% of patients with anti-MDA5 antibodies.
SUMMARY
ILD is most common in the antisynthetase subtype of IIM and can be a chronic indolent or RP- ILD. The MSA and MAAs are associated with different clinical phenotypes of ILD. Treatments typically involve combinations of corticosteroids and other immunosuppressants.
Topics: Humans; Myositis; Autoantibodies; Lung Diseases, Interstitial; Immunosuppressive Agents
PubMed: 37435671
DOI: 10.1097/MCP.0000000000001000 -
Clinica Chimica Acta; International... Jul 2023Polymyositis (PM) and dermatomyositis (DM) are the two subtypes of idiopathic inflammatory myositis and are characterized as symmetrical progressive muscle weakness in... (Review)
Review
Polymyositis (PM) and dermatomyositis (DM) are the two subtypes of idiopathic inflammatory myositis and are characterized as symmetrical progressive muscle weakness in the proximal extremities. PM/DM affect multiple organs and systems, including the cardiovascular, respiratory and digestive tract systems. An in-depth understanding of PM/DM biomarkers will facilitate development of simple and accurate strategies for diagnosis, treatment, and prognosis prediction. This review summarized the classic biomarkers of PM/DM, including anti-aminoacyl tRNA synthetases (ARS) antibody, anti-Mi-2 antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, anti-transcription intermediary factor 1-γ (TIF1-γ) antibody, anti-nuclear matrix protein 2 (NXP2) antibody, among others. Among them, anti-aminoacyl tRNA synthetases antibody is the most classic. In addition, many potential novel biomarkers were also discussed in this review, including anti-HSC70 antibody, YKL-40, interferons, myxovirus resistance protein 2, regenerating islet-derived protein 3-α, interleukin (IL)-17, IL-35, microRNA (miR)-1 and so on. Among the biomarkers of PM/DM described in this review, classic biomarkers have become the mainstream biomarkers to assist clinicians in diagnosis due to their early discovery, in-depth research, and widespread application. The novel biomarkers also have potential and broad research prospects, which will make immeasurable contributions to exploring biomarker-based classification standards and expanding their application value.
Topics: Humans; Dermatomyositis; Polymyositis; Biomarkers; Autoantibodies; Ligases; RNA, Transfer; Retrospective Studies
PubMed: 37329941
DOI: 10.1016/j.cca.2023.117443 -
JAMA Jun 2023Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were...
IMPORTANCE
Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.
OBJECTIVE
To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.
DESIGN, SETTING, AND PARTICIPANTS
This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.
EXPOSURE
Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.
MAIN OUTCOMES AND MEASURES
The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.
RESULTS
Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).
CONCLUSIONS AND RELEVANCE
CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.
Topics: Humans; Antigens, CD19; Leukocytes, Mononuclear; Lung Diseases, Interstitial; Mycophenolic Acid; Myositis; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Cyclophosphamide; Immunosuppressive Agents
PubMed: 37367976
DOI: 10.1001/jama.2023.8753 -
Expert Review of Clinical Immunology 2023Idiopathic inflammatory myopathies (IIMs) represent a diverse group of systemic autoimmune disorders with variable clinical manifestations and disease course. Currently,... (Review)
Review
INTRODUCTION
Idiopathic inflammatory myopathies (IIMs) represent a diverse group of systemic autoimmune disorders with variable clinical manifestations and disease course. Currently, the challenges of IIMs are multifold, including difficulties in timely diagnosis owing to clinical heterogeneity, limited insights into disease pathogenesis, as well as a restricted number of available therapies. However, advances utilizing myositis-specific autoantibodies have facilitated the definition of subgroups as well as the prediction of clinical phenotypes, disease course, and response to treatment.
AREAS COVERED
Herein we provide an overview of the clinical presentations of dermatomyositis, anti-synthetase syndrome, immune-mediated necrotizing myopathy, and inclusion body myositis. We then provide an updated review of available and promising therapies for each of these disease groups. We synthesize current treatment recommendations in the context of case-based construct to facilitate application to patient care. Finally, we provide high-yield, clinical pearls relevant to each of the subgroups that can be incorporated into clinical reasoning.
EXPERT OPINION
There are many exciting developments on the horizon for IIM. As insights into pathogenesis evolve, the therapeutic armamentarium is expanding with many novel therapies in development, holding promise for more targeted treatment approaches.
Topics: Humans; Myositis; Myositis, Inclusion Body; Autoimmune Diseases; Autoantibodies; Disease Progression
PubMed: 37158055
DOI: 10.1080/1744666X.2023.2212162 -
Nature Reviews. Rheumatology Nov 2023The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of systemic autoimmune diseases that affect the skeletal muscles and can also involve the skin,... (Review)
Review
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of systemic autoimmune diseases that affect the skeletal muscles and can also involve the skin, joints, lungs and heart. The epidemiology of IIM is obscured by changing classification criteria and the inherent shortcomings of case identification using healthcare record diagnostic coding. The incidence of IIM is estimated to range from 0.2 to 2 per 100,000 person-years, with prevalence from 2 to 25 per 100,000 people. Although the effects of age and gender on incidence are known, there is only sparse understanding of ethnic differences, particularly in indigenous populations. The incidence of IIM has reportedly increased in the twenty-first century, but whether this is a genuine increase is not yet known. Understanding of the genetic risk factors for different IIM subtypes has advanced considerably. Infections, medications, malignancy and geography are also commonly identified risk factors. Potentially, the COVID-19 pandemic has altered IIM incidence, although evidence of this occurrence is limited to case reports and small case series. Consideration of the current understanding of the epidemiology of IIM can highlight important areas of interest for future research into these rare diseases.
Topics: Humans; Pandemics; Myositis; Muscle, Skeletal; Incidence; Prevalence
PubMed: 37803078
DOI: 10.1038/s41584-023-01033-0 -
Handbook of Clinical Neurology 2024This chapter reviews the association between cancer and the idiopathic inflammatory myopathies (IIM), which includes dermatomyositis (DM), antisynthetase syndrome... (Review)
Review
This chapter reviews the association between cancer and the idiopathic inflammatory myopathies (IIM), which includes dermatomyositis (DM), antisynthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Accumulating evidence shows that the risk of a coexisting malignancy is high in patients with DM, especially among those with anti-Tif1γ autoantibodies. Patients with IMNM and no defined autoantibodies also have an increased risk of malignancy. Recent evidence demonstrates that many IBM patients have increased numbers of circulating CD57+ CD8+ T cells, consistent with a diagnosis of large granular lymphocytic leukemia. In contrast, IMNM patients with anti-SRP or anti-HMGCR autoantibodies as well as patients with ASyS syndrome do not have a definitively increased risk of cancer. Patients who have a cancer treated with one of the immune checkpoint inhibitors can develop myositis (ICI-myositis), sometimes along with myasthenia gravis and/or myocarditis.
Topics: Humans; Myositis; Myositis, Inclusion Body; Autoantibodies; Myasthenia Gravis; Muscle, Skeletal
PubMed: 38494286
DOI: 10.1016/B978-0-12-823912-4.00022-0 -
Current Rheumatology Reports Aug 2023Idiopathic inflammatory myopathies (IIM) are a complex family of autoimmune systemic disorders which often affect muscle and/or skin. IIM cause significant morbidity and... (Review)
Review
PURPOSE OF REVIEW
Idiopathic inflammatory myopathies (IIM) are a complex family of autoimmune systemic disorders which often affect muscle and/or skin. IIM cause significant morbidity and mortality, but optimal treatment is uncertain. This review provides a practical guide for using intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) in the management of IIM, including dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myositis (IMNM), and spontaneous inclusion body myositis (IBM), based on relevant recent literature and experience. We summarize pertinent considerations when using IVIG in special circumstances, including myositis-related dysphagia, interstitial lung disease (ILD), calcinosis cutis, and pregnant patients. This review also discusses IVIG safety, available formulations, and costs.
RECENT FINDINGS
While IVIG has been used de facto for severe IIM for over 30 years, prior clinical trials of IVIG were notably limited. Recently, however, IVIG has proven safe and effective against IIM in several high-impact publications, including a large prospective, randomized placebo-controlled phase III study in DM. IVIG is useful against both muscular and extra-muscular manifestations in many types of IIM. It can be used as a first-line, steroid-sparring agent or as add-on to other treatments, tailored to specific clinical IIM scenarios. It is generally well-tolerated and has good safety profile, but accessibility and cost still limit its use.
Topics: Humans; Immunoglobulins, Intravenous; Dermatomyositis; Prospective Studies; Myositis; Polymyositis; Autoimmune Diseases; Randomized Controlled Trials as Topic; Clinical Trials, Phase III as Topic
PubMed: 37261663
DOI: 10.1007/s11926-023-01105-w -
Nature Reviews. Rheumatology Dec 2023Adult-onset idiopathic inflammatory myopathy (IIM) is associated with an increased cancer risk within the 3 years preceding and following IIM onset. Evidence- and... (Review)
Review
International Guideline for Idiopathic Inflammatory Myopathy-Associated Cancer Screening: an International Myositis Assessment and Clinical Studies Group (IMACS) initiative.
Adult-onset idiopathic inflammatory myopathy (IIM) is associated with an increased cancer risk within the 3 years preceding and following IIM onset. Evidence- and consensus-based recommendations for IIM-associated cancer screening can potentially improve outcomes. This International Guideline for IIM-Associated Cancer Screening provides recommendations addressing IIM-associated cancer risk stratification, cancer screening modalities and screening frequency. The international Expert Group formed a total of 18 recommendations via a modified Delphi approach using a series of online surveys. First, the recommendations enable an individual patient's IIM-associated cancer risk to be stratified into standard, moderate or high risk according to the IIM subtype, autoantibody status and clinical features. Second, the recommendations outline a 'basic' screening panel (including chest radiography and preliminary laboratory tests) and an 'enhanced' screening panel (including CT and tumour markers). Third, the recommendations advise on the timing and frequency of screening via basic and enhanced panels, according to risk status. The recommendations also advise consideration of upper or lower gastrointestinal endoscopy, nasoendoscopy and F-FDG PET-CT scanning in specific patient populations. These recommendations are aimed at facilitating earlier IIM-associated cancer detection, especially in those who are at a high risk, thus potentially improving outcomes, including survival.
Topics: Adult; Humans; Early Detection of Cancer; Positron Emission Tomography Computed Tomography; Neoplasms; Myositis; Autoantibodies
PubMed: 37945774
DOI: 10.1038/s41584-023-01045-w -
Muscle & Nerve Oct 2023Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of... (Review)
Review
Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of high-quality evidence for various specific diseases. To address this, the AANEM created the 2009 consensus statement to provide guidance on the use of IVIG in neuromuscular disorders. Since then, there have been several randomized controlled trials for IVIG, a new FDA-approved indication for dermatomyositis and a revised classification system for myositis, prompting the AANEM to convene an ad hoc panel to update the existing guidelines.New recommendations based on an updated systemic review of the literature were categorized as Class I-IV. Based on Class I evidence, IVIG is recommended in the treatment of chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome (GBS) in adults, multifocal motor neuropathy, dermatomyositis, stiff-person syndrome and myasthenia gravis exacerbations but not stable disease. Based on Class II evidence, IVIG is also recommended for Lambert-Eaton myasthenic syndrome and pediatric GBS. In contrast, based on Class I evidence, IVIG is not recommended for inclusion body myositis, post-polio syndrome, IgM paraproteinemic neuropathy and small fiber neuropathy that is idiopathic or associated with tri-sulfated heparin disaccharide or fibroblast growth factor receptor-3 autoantibodies. Although only Class IV evidence exists for IVIG use in necrotizing autoimmune myopathy, it should be considered for anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase myositis given the risk of long-term disability. Insufficient evidence exists for the use of IVIG in Miller-Fisher syndrome, IgG and IgA paraproteinemic neuropathy, autonomic neuropathy, chronic autoimmune neuropathy, polymyositis, idiopathic brachial plexopathy and diabetic lumbosacral radiculoplexopathy.
Topics: Humans; Child; Immunoglobulins, Intravenous; Dermatomyositis; Neuromuscular Diseases; Myasthenia Gravis; Guillain-Barre Syndrome; Myositis; Polyneuropathies; Myositis, Inclusion Body
PubMed: 37432872
DOI: 10.1002/mus.27922 -
Journal of Autoimmunity Jul 2023The rarity and heterogeneity of idiopathic inflammatory myopathy (IIM) pose challenges for researching IIM in affected individuals. We analyzed integrated transcriptomic...
The rarity and heterogeneity of idiopathic inflammatory myopathy (IIM) pose challenges for researching IIM in affected individuals. We analyzed integrated transcriptomic datasets obtained using muscle tissues from patients with five distinct IIM subtypes to investigate the shared and distinctive cellular and molecular characteristics. A transcriptomic dataset of muscle tissues from normal controls (n = 105) and patients with dermatomyositis (n = 89), polymyositis (n = 33), inclusion body myositis (n = 121), immune-mediated necrotizing myositis (n = 75), and anti-synthetase syndrome (n = 18) was used for differential gene-expression analysis, functional-enrichment analysis, gene set-enrichment analysis, disease-module identification, and kernel-based diffusion scoring. Damage-associated molecular pattern-associated pathways and neutrophil-mediated immunity were significantly enriched across different IIM subtypes, although their activities varied. Interferons-signaling pathways were differentially activated across all five IIM subtypes. In particular, neutrophil extracellular trap (NET) formation was significantly activated and correlated with Fcγ R-mediated signaling pathways. NET formation-associated genes were key for establishing disease modules, and FCGRs, C1QA, and SERPINE1 markedly perturbed the disease modules. Integrated transcriptomic analysis of muscle tissues identified NETs as key components of neutrophil-mediated immunity involved in the pathogenesis of IIM subtypes and, thus, has therapeutically targetable value.
Topics: Humans; Dermatomyositis; Extracellular Traps; Myositis; Polymyositis; Myositis, Inclusion Body
PubMed: 37220716
DOI: 10.1016/j.jaut.2023.103063