An exploratory study of circulating cytokines and chemokines in patients with muscle disorders proposes CD40L and CCL5 represent general disease markers while CXCL10 differentiates between patients with an autoimmune myositis

213th ENMC International Workshop: Outcome measures and clinical trial readiness in idiopathic inflammatory myopathies, Heemskerk, The Netherlands, 18–20 September 2015

Inflammatory myopathies are a heterogeneous group of immune-mediated diseases that involve the skeletal muscle as well as many other organs. In addition to a histological diagnosis at muscle biopsy, the clinical phenotypes of inflammatory myopathies can be defined by the presence of various autoantibodies that are originally detected by RNA or protein immunoprecipitation. However, the correlation between histological features and autoantibodies has not been fully elucidated. Immune-mediated necrotizing myopathy (IMNM), which is characterized by significant necrotic and regeneration muscle fibers with minimal or no inflammatory cell infiltration, is associated with the presence of autoantibodies. IMNM is now classified as a distinct category of inflammatory myopathies, separate from polymyositis, dermatomyositis, and sporadic inclusion body myositis. Here, we divided the autoantibodies of inflammatory myopathies into the following categories: those associated with IMNM, those with activity against aminoacyl transfer RNA synthetase, those associated with dermatomyositis, and those related to other disorders, including overlap syndrome, inclusion body myositis, and primary biliary cirrhosis. The detection of autoantibodies against signal recognition particle or 3-hydroxy-3-methylglutaryl-coenzyme A reductase is useful for the diagnosis of IMNM. The screening of autoantibodies has clinical relevance for managing patients with inflammatory myopathies.

ObjectivesTo explore the link between moderate to severe oropharyngeal dysphagia and cancer in autoimmune myositis (AIM) other than inclusion body myositis (IBM).MethodsThe medical records of patients with AIM seen in rheumatology in two university hospitals from January 2000 to December 2022 were retrospectively reviewed. Using an updated AIM subclassification, patients were classified by expert opinion as pure dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), scleromyositis, lupomyositis, anti-MDA-5 syndrome, antisynthetase syndrome (ASyS) or polymyositis syndrome. Objective oropharyngeal dysphagia at myositis diagnosis was defined by an abnormal videofluoroscopic swallowing study and/or the need for percutaneous gastrojejunostomy. The presence of cancer within 3 years of myositis diagnosis was recorded.ResultsPure DM accounted for 50% (n = 20/40) of the cases of objective oropharyngeal dysphagia, while anti-MDA-5 syndrome and ASyS together represented 8% (n = 3/40). Cancers occurred predominantly in pure DM (n = 27/33), and rarely in scleromyositis (n = 1/53), anti-MDA-5 syndrome and ASyS (n = 0/62). Among patients 50 years of age or older with pure DM (n = 50), cancer was present in 40% (n = 4/10) of patients with no muscle weakness, 45% (n = 10/22) in those with proximal weakness alone, 44% (n = 4/9) in those with moderate dysphagia and 100% of those with severe dysphagia (n = 9/9) (p = 0.02 by two-sided Fisher’s exact test).ConclusionRecognizing scleromyositis, anti-MDA-5 and ASyS as distinct from pure DM improves risk stratification for cancer screening. In patients ≥ 50 years with pure DM, severe oropharyngeal dysphagia is strongly associated with cancer, suggesting a paraneoplastic myopathy with an ineffective anticancer immune response.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13075-025-03662-0.

Preface Part I. Overview of Pathologic and Pathogenic Comparison Between Sporadic Inclusion-Body Myositis and Hereditary Inclusion-Body Myopathies: 1. Newest approaches to diagnosis and pathogenesis of sporadic inclusion-body myositis and hereditary inclusion-body myopathies, including molecular-pathologic similarities to Alzheimer disease Part II. Historical Perspective: 2: Evolving concepts of inclusion-body myositis Part III. Sporadic Inclusion-Body Myositis - Clinical and Diagnostic Considerations: 3: Sporadic inclusion-body myositis: Clinical and laboratory features and diagnostic criteria 4: Inclusion-body myositis: natural history 5: Uncommon clinico-pathological forms of sporadic inclusion-body myositis: Report of four cases 6: Inclusion-body myositis: pathological changes 7: Unusual pathological forms of inclusion-body myositis, and neuromuscular disorders with IBM-like changes 8: Electrophysiological findings in inclusion-body myositis 9: Genetic factors in sporadic inclusion-body myositis Part IV. Hereditary Inclusion-Body Myopathies - Clinical and Diagnostic Considerations: 10: Hereditary inclusion-body myopathy in Jews of Persian origin: Clinical and laboratory data 11. Hereditary inclusion-body myopathy (h-IBM) with quadriceps sparing: epidemiology and genetics 12: Familial autosomal-recessive inclusion-body myositis with asymptomatic leukoencephalopathy 13: Welander distal myopathy - clinical, pathophysiological, and molecular aspects 14. Tibial muscular dystrophy - clinical, genetic, and morphological characteristics 15. Distal myopathy with rimmed vacuoles, inclusion-body myositis and related disorders in Japan 16. Inclusion-body myopathies 17. Is the muscle fiber in inclusion body-myositis an antigen-presenting cell of an innocent bystander? 18. Viruses, immunodeficiency and inclusion-body myositis 19. Myonuclear abnormalities may play a central role in the pathogenesis of muscle fiber damage in inclusion-body myositis 20. Nuclear degeneration and rimmed vacuole formation in neuromuscular disorders 21. Mitochondrial alterations in sporadic inclusion-body myositis 22. mtDNA analysis in muscle of patients with sporadic inclusion-body myopathy Part V. Treatment: 23. Evaluation of treatment for sporadic inclusion-body myositis 24. Personal experience in treating sporadic inclusion-body myositis Subject index.

Idiopathic inflammatory myopathies (IIM), also known as autoimmune myositis, are a rare group of auto-immune-associated muscle disorders with a heterogenous yet highly specific spectrum of muscular and extra-muscular involvement. Historically, IIM are classified into three major subgroups including polymyositis, dermatomyositis, and inclusion body myositis (IBM) mainly by their clinical or pathological features or both in combination [1–10]. The discovery of myositis-specific antibodies (MSA) and mounting evidence of their association with relatively specific clinicopathological features together with transcriptomics findings gradually change the trend of IIM classification over the past four decades to clinicoseropathological criteria, which classifies IIM into four major subgroups (Table 3.1) dermatomyositis, IBM, immune-mediated necrotizing myopathy (IMNM), and recently proposed as a separate entity—antisynthetase syndrome (ASS), whereas the existence of polymyositis as a distinct entity has been questioned [11].

POS0183 SIGLEC1 AS A TYPE I INTERFERON BIOMARKER IN IDIOPATHIC INFLAMMATORY MYOPATHIES

OMICs AND AI APPROACHES FOR MUSCLE DISEASES: O.08 Deep convolutional-neural-network can differentiate twelve major muscular diseases better than human

Activation of the type 1 interferon (IFN1) pathway is a prominent feature of dermatomyositis (DM) muscle and may play a role in the pathogenesis of this disease. However, the relevance of the IFN1 pathway in patients with other types of myositis such as the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM) is largely unknown. Moreover, the activation of the type 2 interferon (IFN2) pathway has not been comprehensively explored in myositis. In this cross-sectional study, our objective was to determine whether IFN1 and IFN2 pathways are differentially activated in different types of myositis by performing RNA sequencing on muscle biopsy samples from 119 patients with DM, IMNM, AS, or IBM and on 20 normal muscle biopsies. The expression of IFN1- and IFN2-inducible genes was compared between the different groups. The expression of IFN1-inducible genes was high in DM, moderate in AS, and low in IMNM and IBM. In contrast, the expression of IFN2-inducible genes was high in DM, IBM, and AS but low in IMNM. The expression of IFN-inducible genes correlated with the expression of genes associated with inflammation and muscle regeneration. Of note, ISG15 expression levels alone performed as well as composite scores relying on multiple genes to monitor activation of the IFN1 pathway in myositis muscle biopsies. IFN1 and IFN2 pathways are differentially activated in different forms of myositis. This observation may have therapeutic implications because immunosuppressive medications may preferentially target each of these pathways.

P.15Myopathies featuring early or prominent dysphagia

Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity

TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.

Serum cytokine and chemokine profiles in patients with immune-mediated necrotizing myopathy

Sporadic inclusion body myositis (IBM) is a late onset idiopathic inflammatory myopathy, characterized by rimmed vacuoles and cytoplasmic or nuclear tubulofilamentous inclusions. Clinical features are proximal and/or distal weakness, frequent muscle atrophy, hyporeflexia and poor responsiveness to steroid treatment. The involvement of peripheral nerve in both sporadic and familial IBM is a debated issue. Among six cases (five men; age range: 65–82 yrs.) of muscle biopsy proven sporadic IBM, we found variable neuropathic changes. Myogenic/neurogenic mixed EMG pattern was detected in four patients. Sensory and motor nerve conduction studies showed abnormalities consistent with axonal multiple mononeuropathy in three and with axonal polyneuropathy in two patients, whereas one subject had no neurogenic findings. However, the degree of peripheral nerve impairment was usually mild and not related to severity of myopathy. Sural nerve biopsy was performed in the case with more prominent clinical and electrophysiological polyneuropathy. Moderate homogeneous loss of myelinated fibers, with recurrent regeneration clusters and atrophic/degenerating axons were observed. No segmental demyelination was present. In spite of marked inflammatory changes in muscle, neither mononuclear cell infiltrates nor filamentous inclusions were detected in nerve. Similarly, whereas paracrystalline mitochondrial inclusions were observed in muscle, minor but recurrent mitochondrial changes were detected in nerve. Muscle mitochondrial abnormalities have been reported about twice in IBM compared with other inflammatory myopathies. A relation of this finding with high incidence of associated peripheral neuropathy in IBM and mitochondrial myopathies has been hypothesized. On the other hand, the follow‐up of our patients shows improvement of nerve conduction values in clinically responders to intravenous immunoglobulin treatment, suggesting a significant role of immune processes for the pathogenesis of nerve damage in IBM.

ObjectiveTo define the clinicopathologic features and diagnostic utility associated with anti‐cytosolic 5′‐nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).MethodsAnti‐NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune‐mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.ResultsOf 593 patients, anti‐NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti‐NT5C1A antibody seropositive patients had more cytochrome oxidase‐negative fibers compared with anti‐NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti‐NT5C1A antibody, three patients (21%) converted to positive. Anti‐NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs.InterpretationAnti‐NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non‐IBM IIMs and it does not correlate with any prognostic factors or survival.

ObjectiveTo investigate the relevance of dysfunctional T cells in immune-mediated myopathies. We analyzed T-cell exhaustion and senescence, in the context of programmed cell death protein 1 (PD1)-related immunity in skeletal muscle biopsies from patients with immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis (sIBM), and myositis induced by immune checkpoint inhibitors (irMyositis).MethodsSkeletal muscle biopsies from 12 patients with IMNM, 7 patients with sIBM, and 8 patients with irMyositis were analyzed by immunostaining and immunofluorescence as well as by quantitative PCR. Eight biopsies from nondisease participants served as controls.ResultsCD3+CD8+ T cells in biopsies from IMNM, sIBM, and irMyositis were largely PD1-positive, while CD68+ macrophages were sparsely positive to the ligand of programmed cell death protein 1 (PD-L1). The sarcolemma of myofibers was PD-L2+ and was colocalized with major histocompatibility complex (MHC) class I. CD68+ macrophages were colocalized with PD-L2. Senescent T cells were strongly enriched in skeletal muscle of sIBM, revealing a distinct immunologic signature. Biopsies from patients with irMyositis showed mild signs of senescence and exhaustion.ConclusionPersistent exposure to antigens in IMNMs and sIBM may lead to T-cell exhaustion, a process controlled by the PD1 receptor and its cognate ligands PD-L1/PD-L2. To our knowledge, these data are the first evidence of presence of dysfunctional T cells and relevance of the PD1 pathway in IMNM, sIBM, and irMyositis. These findings may guide the way to a novel understanding of the immune pathogenesis of immune-mediated myopathies.