Background/Purpose: JDM is an autoimmune disease of skin and muscle. We investigated genetic factors, autoantibodies, and clinical features in JDM.

Methods: Subjects came from 2 large institutions (n=61). Techniques included Southern blot (C4 gene copy number [GCN]), NovaSeq6000 S2 PE150bp whole exome sequencing (WES) with 100x median coverage, and flow cytometry (complement deposition).

Results: C4 GCN was associated with pathology at diagnosis. Lower C4A and C4L but higher C4B and C4S GCN were associated with elevated muscle enzymes (p=0.034, p=0.020, 0.026, and p=0.010). Higher C4S GCN correlated with lower muscle strength (p=0.039) and lower C4L with abnormal MRI (p= 0.039). Higher C4S GCN was associated with including arthritis (p=0.032), systemic symptoms (p=0.020), and dysphagia (p=0.0078). Patients with JDM had increased complement activation including higher levels of circulating C3a, C4a, and C5a (p< 0.0001, p=0.028, and p< 0.0001) and increased RBC-bound C4d (p< 0.0001), particularly in patients with C4A insufficiency and higher C4B GCN (p=0.0003 and p=0.003). WES identified genes involved in endothelial/skin and muscle homeostasis, mitochondrial function, and transcription. These pathways are targeted by autoantibodies. Genes mutated in our patients included titin (muscle protein) in 30% and solute carrier protein 25 (mitochondrial transport) in 22%.

Conclusion: Our data suggest that C4 plays a key role in JDM and that autoantibodies may develop against mutated proteins involved in mucosal, skin, and muscle homeostasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proposed-pathways-involved-in-the-pathogenesis-of-juvenile-dermatomyositis-jdm/