Children with Interstitial Lung Disease Due to MDA5-Juvenile Dermatomyositis Have Elevated Interferon-Stimulated Genes

Background: Anti-Melanoma Differentiation Associated Protein 5 (MDA5) antibody-positive juvenile dermatomyositis (JDM) represents a distinct phenotype characterized by minimal myositis, skin ulceration, and high incidence of interstitial lung disease (ILD). A subset of anti-MDA5 patients has rapidly progressive ILD (RP-ILD). The type I interferon pathway is activated in JDM patients but has not been investigated specifically in children's ILD. Methods: Retrospective review was completed on patients <18 years with JDM, ILD, and positive anti-MDA5 antibodies (MDA5-JDM) and compared to JDM patients with other myositis-specific antibodies (other-JDM), none of which had ILD. Quantitative real-time PCR was used to measure the expression of 6 interferonstimulated genes (ISGs) in peripheral blood cells. Results: Thirteen MDA5-JDM were compared to 10 other-JDM (5 anti-TIF1/, 3 anti-NXP-2, 2 anti-Mi-2). MDA5-JDM were more frequently male (54% vs 30%). At diagnosis, MDA5-JDM were younger (7.3 vs 8.6 years) and had more respiratory symptoms (78% vs 20%), including cough and shortness of breath. All JDM patients had rashes, with Gottron's papules and erythema most common. However, ulcerations were more common in MDA5-JDM (46% vs 10%), as was arthritis (77% vs 50%). Surprisingly, MDA5-JDM had more weakness despite lower muscle enzymes (mean creatine kinase 107.5 vs 2201 U/L). All MDA5-JDM had chest CT scans which showed ground-glass opacities (69%), air space disease (61%), and pneumomediastinum (46%). One other-JDM had a normal chest CT. Five MDA5-JDM required supplemental oxygen: 1 nasal cannula, 2 high-frequency oscillatory ventilation, and 2 extra-corporeal membrane oxygenation. No other-JDM required respiratory support. Eight MDA5-JDM had pulmonary function testing (PFTs). There was a diffusion defect in 75% and a restrictive pattern in 25%, compared to normal PFTs in 3 other-JDM. At last follow-up (range 6 months-5 years), diffusion defects (60%) and dyspnea on exertion (30%) were still present. Four MDA5-JDM had RP-ILD, with a mean age at diagnosis 2.7 years, significantly lower than the other MDA5-JDM (11.2 years). Three of the 4 died, and the surviving patient required 14 months of mechanical ventilation. Relative quantification of ISGs in MDA5-JDM showed elevated values not seen in controls or other-JDM. Patients with high disease activity at the time of sampling had higher ISG levels.