Dr. Pachman's translational and collaborative team studies juvenile dermatomyositis (JDM), an often chronic pediatric systemic vasculopathy of unknown etiology. JDM is associated with inflammation in the skin, as well as in the proximal musculature resulting in extensive weakness. The goal of their studies is to discover biomarkers of disease activity to guide the utilization and/or creation of more effective therapies. Dr. Pachman's laboratory has identified genetic and environmental factors that not only play a role in the onset of symptoms, but also govern the child's outcome. For example, the TNF-α-308 promoter A polymorphism is associated with a prolonged disease course requiring immunosuppressive therapy for at least three years. Increased production of the protein, TNF-α, by JDM children with the A allele is seen throughout the disease course, in contrast to serum levels of IFN-α activity, which are usually elevated early in the disease. Gene expression micro array studies of untreated children's diagnostic muscle biopsies disclosed a strong dysregulation of IFN-α induced genes in JDM, similar to an anti-viral immune model, which also shares some features of the IFN-α signature characteristic of systemic lupus erythematosus (SLE). This chronic inflammatory setting promotes the development of often debilitating pathologic calcifications, which have been clearly defined as dystrophic in nature, displaying an increased mineral/matrix ratio, and extensive integrin involvement.
Other epidemiological factors may modify the child's disease course. Specifically, a period of untreated active disease greater than two months is associated with genes controlling vascular remodeling, which appear to differ from genes expressed by muscle from children not fully responsive to therapy. Epigenetic and miRNA studies of the diagnostic muscle biopsies indicate further critical differences when appropriate treatment is delayed, in addition the child's gender skews gene-gene interactions. The search for clinically useful biomarkers of immune activation identified CD3-negative natural killer cells, as well as von Willebrand factor antigen, released from damaged endothelial cells. Endothelial damage is also reflected in loss of nailfold capillary end row loops the laboratory developed a method to measure changes over time and are associated, not only with disease chronicity, but lack of absorption of prednisone (when given by mouth). Finally, site specificity is also under investigation: the pathophysiology of the cutaneous inflammation differs from that of muscle mast cells are increased in both lesional and non-lesional skin in untreated children and scarce in their paired muscle samples and controls.
Dr. Pachman is the Principle Investigator and Director of the Cure JM Foundation's "Program of Excellence in Myositis Research" and has cared for over 400 children with JDM and other forms of inflammatory myopathy. The patient derived material has been obtained with consent for genetic research and includes diagnostic muscle and skin biopsies, sequential sera, peripheral blood lymphocytes, lymphocyte culture supernatant fluid, and samples of dystrophic calcifications. This repository is keyed to a sequential, coded, specific myositis database containing over a 1,000 variables/child. In summary, this collaborative and intensive research effort broadens the clinical, genetic and immunological characterization of the child with JDM, which helps to guide current therapy and may lead to the consideration of novel targeted interventions.