Complement C4 gene copy number variations and polymorphisms, autoantibodies, and clinical manifestations of juvenile dermatomyositis– a multi-center study

Juvenile dermatomyositis (JDM) is an autoimmune myopathy characterized by rash and muscle weakness. Complement C4 gene copy number (GCN) variation is a known risk factor for JDM. JDM patients often develop autoantibodies. We investigated the relationship between C4 GCN, clinical features, and antibody development. Subjects were recruited (n=255) from the US, Sweden, and the Czech Republic. C4 GCN was determined by real time PCR. Comparative analyses were performed via student’s t test or Mann Whitney U test. Correlation was assessed via linear regression or Fisher’s exact test. All studies were IRB approved, and informed consent was obtained. C4 GCN correlated with muscle pathology and extra-muscular disease at diagnosis. Lower C4A and C4L GCN were associated with a higher number of abnormal muscle enzymes (p=0.0062 and p=0.0029), while the opposite was true for C4S (p=0.024). Higher C4S GCN correlated with lower muscle strength scores (p=0.039). Lower C4L correlated with abnormal MRI (p= 0.042). C4B GCN correlated with dysphagia (p=0.035). Higher GCN of C4S was a risk factor for arthritis (p=0.032), systemic symptoms (p=0.020), and dysphagia (p=0.0078). C4 GCN was associated with myositis-specific (MSA) and myositis-associated (MAA) antibodies. Patients with homozygous C4A deficiency were more likely to test positive for anti-NXP2 (OR 20.0, p=0.011), and C4A GCN was lower in anti-NXP2 positive subjects (p=0.030). A higher C4B GCN correlated with positive MAA (p=0.043). Here, we show that low C4A/C4L GCN and high C4B/C4S GCN correlate with worse muscle disease, extra-muscular pathology, and autoantibodies. Our data suggest that complement C4 may play a key role in the ongoing pathogenesis of JDM. Supported by grants from NIH (R21 AR070509) and the CureJM Foundation