Mitochondrial abnormalities a prognostic marker for juvenile dermatomyositis
ATLANTA — Patients with juvenile dermatomyositis demonstrate obvious mitochondrial abnormalities in the tissue and periphery, supporting the use of anti-mitochondrial antibodies as a prognostic marker, according to data presented at ACR/ARP 2019.
“Though mainly found intracellularly, we recently observed mitochondrial extrusion upon cell death, contributing to inflammation and organ damage in lupus-prone mice,” Christian Lood, PhD, MSc, of the University of Washington in Seattle, told attendees. “Of note, mitochondria are immunogenic, promoting development of anti-mitochondrial antibodies. Mitochondrial remnants, including DNA, are observed in the circulation of many systemic diseases, including lupus, and thought to partake in the disease pathogenesis. However, the role of mitochondrial extrusion in children with juvenile dermatomyositis has not been addressed.”
“Can we find extracellular mitochondrial protein and DNA in blood from children [with juvenile dermatomyositis]?” he added. “Do children with juvenile dermatomyositis develop anti-mitochondrial antibodies? Do biomarkers of extracellular mitochondria reflect muscle damage in calcinosis in juvenile dermatomyositis?”
To analyze the markers of mitochondrial extrusion, including mitochondrial DNA and anti-mitochondrial antibodies, in patients with juvenile dermatomyositis, as well as their possible clinical utility, Lood and colleagues studied 90 children with various conditions and 22 healthy peers. Participants included 10 patients with pediatric lupus, seven with polymyositis, 61 with juvenile dermatomyositis and 12 with ribonucleoprotein-positive myositis.
In their analysis, the researchers used a flow cytometry technique along with an in-house quantitative polymerase chain reaction assay. In addition, they associated mitochondrial markers with disease activity score, calcinosis and autoantibody profiles. Lood and colleagues evaluated muscle biopsies using electron microscopy.
According to the researchers, electron microscopy imaging demonstrated “profound mitochondrial abnormalities” in the muscle tissue of patients with juvenile dermatomyositis, Lood said. These included intramitochondrial calcification associated with degenerate muscle fibers and mitochondrial extrusion. Patients with juvenile dermatomyositis also demonstrated increased levels of cell-free mitochondrial DNA (P = .02), but not genomic DNA (P = .09) in peripheral blood, particularly among children with calcinosis (P = .002), compared with healthy controls.
In addition, Western blot analysis determined that patients with juvenile dermatomyositis possessed autoantibodies that reacted toward mitochondrial antigens of 60 kDa. According to Lood, this is similar to what was reported in juvenile systemic lupus erythematosus. The flow cytometry analysis found that 40% of patients with juvenile dermatomyositis were positive for anti-mitochondrial antibodies (P < .001). Levels of anti-mitochondrial antibodies in turn correlated with the presence of antigen — mitochondrial DNA, for example — in peripheral blood (r = 0.28; P < .05), immune complex levels (r = 0.56; P < .0001) and complement C4 consumption (r = –0.59; P = .01).
When activated with mitochondrial immune complex, neutrophils induced IL-8 production P < .01) and began forming neutrophil extracellular traps (P < .05). According to Lood, this demonstrated the inflammatory potential of mitochondrial immune complex levels. The presence of anti-mitochondrial antibodies was associated with calcinosis (OR = 6.1; P = .006). In addition, anti-mitochondrial antibodies were elevated before the clinical diagnosis of calcinosis was made (OR = 11.1; P < .05), with an 80% sensitivity and a specificity of 73.5%, to identify calcinosis-prone individuals within the group of children with juvenile dermatomyositis.
According to Lood, these findings suggest anti-mitochondrial antibodies may be used as a prognostic marker for calcinosis development in juvenile dermatomyositis.
“Intramitochondrial calcification is muscle in present in children [with juvenile dermatomyositis],” Lood said. “As are extracellular mitochondria. Novel mitochondrial biomarkers are associated with calcinosis, suggesting potential novel therapeutic targets in juvenile dermatomyositis.” – by Jason Laday
Duvvuri B. Mitochondrial contribution to juvenile dermatomyositis pathogenesis. Presented at: American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; Nov. 9-13, 2019; Atlanta.
Disclosure: Lood reports no relevant financial disclosures.