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Novel phenotypes of immune-mediated necrotizing myopathy identified independent of myositis-specific antibody specificity that improve prognostic stratification

ABSTRACT: Immune-mediated necrotizing myopathy (IMNM) is a severe autoimmune myopathy with high clinical heterogeneity. Current classification relies on myositis-specific antibodies (MSA: anti-HMGCR, anti-SRP) but fails to explain differences in manifestations, interstitial lung disease (ILD) incidence, and survival. We enrolled 133 IMNM patients, used unsupervised machine learning (MSA-independent) to identify three phenotypes: Phenotype 1 (56.4%, muscle weakness, favorable prognosis), Phenotype 2 (10.5%, high muscle damage indicators, intermediate prognosis), Phenotype 3 (33.1%, high ILD/mortality, poor prognosis). Label-free DIA quantitative proteomics on these phenotypes and noninflammatory controls revealed distinct protein expression patterns, providing molecular evidence for IMNM subtyping, mechanism exploration, and prognosis evaluation.

ORGANISM(S): Homo Sapiens

SUBMITTER: Xuefan Yu

PROVIDER: PXD078154 | iProX | Wed May 06 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX

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Novel phenotypes of immune-mediated necrotizing myopathy identified independent of myositis-specific antibody specificity that improve prognostic stratification.

Wei Xiaojing X Sun Hui H Pang Zhidan Z Bai Na N Guo Tiantian T Nie Changpu C Yang Xuan X Lu Zhen Z Bao Liye L Miao Jing J Yu Xuefan X

Frontiers in immunology 20260514

<h4>Aim</h4>To systematically investigate the clinical characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM), and to explore the proteomic landscape associated with different clinical phenotypes.<h4>Methods</h4>A total of 133 IMNM patients were enrolled in this retrospective study. The clinical features and outcomes were compared across three subgroups: anti-HMGCR-positive, anti-SRP-positive, and seronegative patients. Unsupervised machine learning algorithms ...[more]

PMID: 42220524

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Project description:Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes. References: Hallal, Mahmoud, Sophie Braga-Lagache, Jovana Jankovic, Cedric Simillion, Rémy Bruggmann, Anne-Christine Uldry, Ramanjaneyulu Allam, Manfred Heller, and Nicolas Bonadies. 2021. “Inference of Kinase-Signaling Networks in Human Myeloid Cell Line Models by Phosphoproteomics Using Kinase Activity Enrichment Analysis (KAEA).” BMC Cancer 21 (1): 789.

Project description:Background: A 58-year-old male with anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD) underwent bilateral lung transplantation (LTx) but experienced ILD progression and myositis worsening 38 weeks post-transplant, despite glucocorticoids, tacrolimus, and mycophenolic acid treatment. High-dose glucocorticoids led to adverse effects and ILD exacerbation upon tapering. Objective: To identify persistent inflammatory pathways despite anti-rejection therapy. Methods: Two sets of single-cell RNA-seq (scRNA-seq) analyses were conducted on peripheral blood mononuclear cells (PBMCs) from our patient who experienced recurrent ASS-ILD following bilateral LTx: one before regimen adjustment and one after. The goal these analyses is to investigate systemic inflammatory profiles. Results: In comparison to five ASS-ILD patients without LTx, our patient following bilateral LTx (before regimen adjustment) displayed a higher proportion of CD14⁺ and CD16⁺ monocytes, alongside reduced T, B, and NK cells. Notably, interferon- and JAK-STAT–associated pathways were significantly enriched, as evidenced by marked up-regulation of key genes (e.g. JAK1, JAK2, STAT1, STAT2, STAT3, IL4R, IL6R) in the patient’s monocytes. Elevated serum ferritin levels and the enrichment of macrophage and neutrophil activation pathways further underscored hyperactivation of the mononuclear phagocyte system. Due to poor tolerance of high-dose steroids, limited efficacy of tacrolimus and MPA, and the need to manage post-transplant rejection while controlling ASS, the patient’s regimen was modified. Considering the activation of the mononuclear phagocyte system in the patient, tacrolimus was replaced with cyclosporine A, which is more widely used in macrophage activation syndrome (target trough concentration 120-150 ng/ml). Given the significant activation of the interferon and JAK-STAT pathways in the patient’s activated monocytes, we replaced EC-MPS with the Janus kinase inhibitor (JAKi) tofacitinib at 5 mg twice daily. Short-term high-dose glucocorticoids (methylprednisolone 120 mg/d for 3 days) were also administered before rapid tapering. After regimen adjustment, scRNA-seq was conducted again, which indicated a reduction in CD14⁺ and CD16⁺ monocytes, with T, B, and NK cells rebounding. Neutrophils, characterized by high S100A8, S100A9, and DEFA3 expression, became more prominent. Interferon-related gene expression decreased in monocytes and neutrophils, indicating successful suppression of the interferon pathway. Conclusions: We presented a complicated case of a patient with early recurrence of underlying ASS-ILD after bilateral lung transplantation. We used two sets of scRNA-seq analyses to investigate the systemic inflammatory responses.

Dataset Information

Novel phenotypes of immune-mediated necrotizing myopathy identified independent of myositis-specific antibody specificity that improve prognostic stratification

Publications

Novel phenotypes of immune-mediated necrotizing myopathy identified independent of myositis-specific antibody specificity that improve prognostic stratification.

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