Discovery of tissue-specific proteomic signatures in juvenile dermatomyositis highlights pathways reflecting persistent disease activity, clinical heterogeneity, and myositis-specific autoantibody subtype

Jessica Neely¹, Sara E Sabbagh², Jeffrey Dvergsten³, Chioma Madubata⁴, Celine C Berthier⁵, Zilan Zheng⁴, Christine Goudsmit⁶, Sophia Matossian⁶, Sean P Ferris⁷, Gabriela K Fragiadakis⁸, Marina Sirota⁹, J Michelle Kahlenberg¹⁰, Hanna Kim¹¹, Jessica L Turnier⁶; CARRA Registry Investigators and CARRA Translational Medicine for Juvenile Myositis Working Group

Affiliations

¹ Department of Pediatrics, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: Jessica.Neely@ucsf.edu.
² Department of Pediatrics, Division of Rheumatology, The Medical College of Wisconsin, Milwaukee, WI, USA.
³ Department of Pediatrics, Division of Rheumatology, Duke University, Durham, NC, USA.
⁴ Department of Pediatrics, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Pediatrics, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Bakar Computational Health Science Institute, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹¹ Juvenile Myositis Pathogenesis and Therapeutics Unit, National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.

PMID: 40915939
DOI: 10.1016/j.ard.2025.07.020

Free article

Discovery of tissue-specific proteomic signatures in juvenile dermatomyositis highlights pathways reflecting persistent disease activity, clinical heterogeneity, and myositis-specific autoantibody subtype

Jessica Neely et al. Ann Rheum Dis. 2025.

Free article

. 2025 Sep 6:S0003-4967(25)04291-8.

doi: 10.1016/j.ard.2025.07.020. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: Jessica.Neely@ucsf.edu.
² Department of Pediatrics, Division of Rheumatology, The Medical College of Wisconsin, Milwaukee, WI, USA.
³ Department of Pediatrics, Division of Rheumatology, Duke University, Durham, NC, USA.
⁴ Department of Pediatrics, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Pediatrics, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, USA.
⁹ Bakar Computational Health Science Institute, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹¹ Juvenile Myositis Pathogenesis and Therapeutics Unit, National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.

PMID: 40915939
DOI: 10.1016/j.ard.2025.07.020

Abstract

Objectives: Juvenile dermatomyositis (JDM) is a heterogeneous autoimmune condition needing targeted treatment approaches and improved understanding of molecular mechanisms driving clinical phenotypes. We utilised exploratory proteomics from a longitudinal North American cohort of patients with new-onset JDM to identify biological pathways at disease onset and follow-up, tissue-specific disease activity, and myositis-specific autoantibody (MSA) status.

Methods: We measured 3072 plasma proteins (Olink panel) in 56 patients with JDM within 12 weeks of starting treatment (from the Childhood Arthritis and Rheumatology Research Alliance Registry and 3 additional sites) and 8 paediatric controls. Twenty-four patients with JDM who had 6-month follow-up samples were assessed. We identified differentially expressed proteins (DEPs) between groups by fitting linear mixed effects models and associated DEPs with validated disease activity measures. We assessed for cell/tissue specificity using the Human Protein Atlas and JDM muscle single nuclei and skin single-cell transcriptomic datasets. Differences within MSA subgroups were also analysed.

Results: We uncovered persistent dysregulation of innate immune activation, cell death, and redox signalling at 6 months despite multidrug immunosuppression. By leveraging tissue and cell-specific proteomes, we identified overrepresentation of circulating endothelial proteins associated with disease activity and verified endothelial cell marker expression in JDM muscle and skin. We discovered pathways associated with MSA subtypes that reflect JDM phenotypes. NXP2+ JDM-associated proteins reflected angiogenesis and extracellular matrix remodelling and were expressed in endothelial cells and fibroblasts. MDA5+ JDM was associated with circulating type III interferon and surfactant proteins.

Conclusions: These proteomic findings will inform future biomarker and treatment development considering the unique tissue- and autoantibody-associated inflammation in JDM.

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Conflict of interest statement

Competing interests JLT and JN report financial support was provided by CARRA Inc. JLT, JN, JMK, SPF, and GKF report financial support was provided by The Chan Zuckerberg Initiative. JLT, JN, HK, JMK, GKF, and MS report financial support was provided by National Institutes of Health. JN and JD report financial support was provided by Cure JM Foundation. HK reports a relationship with Cabaletta Bio Inc that includes: consulting or advisory. JLT reports a relationship with Cabaletta Bio Inc that includes: consulting or advisory. HK reports a relationship with Bristol Myers Squibb Co that includes: nonfinancial support. JMK reports a relationship with Q32 Bio that includes: funding grants. JMK reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and funding grants. JMK reports a relationship with Ventus Therapeutics Inc that includes: consulting or advisory and funding grants. JMK reports a relationship with ROME Therapeutics that includes: consulting or advisory and funding grants. JMK reports a relationship with Janssen Therapeutics that includes: funding grants. JMK reports a relationship with AstraZeneca that includes: consulting or advisory. JMK reports a relationship with Biogen that includes: consulting or advisory. JMK reports a relationship with Eli Lilly that includes: consulting or advisory. JMK reports a relationship with EMD Serrano that includes: consulting or advisory. JMK reports a relationship with Gilead Sciences that includes: consulting or advisory. JMK reports a relationship with GlaxoSmithKline Inc that includes: consulting or advisory. JMK reports a relationship with Aurinia Pharmaceuticals Inc that includes: consulting or advisory. HK reports a relationship with Eli Lilly and Company that includes: nonfinancial support. JD consults for Rare Disease Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Discovery of tissue-specific proteomic signatures in juvenile dermatomyositis highlights pathways reflecting persistent disease activity, clinical heterogeneity, and myositis-specific autoantibody subtype

Affiliations

Discovery of tissue-specific proteomic signatures in juvenile dermatomyositis highlights pathways reflecting persistent disease activity, clinical heterogeneity, and myositis-specific autoantibody subtype

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources