Pathogenic Mechanisms in Spondyloarthritis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Genetic Contributions to Early Onset Axial Spondyloarthritis We continue to evaluate children with early onset AxSpA and using a trio-based approach, look for rare genetic variants or mutations that may contribute to disease onset and phenotype. Several candidate genes have been identified. Progress has been slowed by COVID-related restrictions on patients and family members being seen in the Clinical Center, but the project continues. The Interaction Between HLA-B27 and ERAP1 ERAP1 knockout rats have been generated and used to study how loss of ERAP1 function affects the development of experimental spondyloarthritis in HLA-B27 transgenic rats. This model mimics the epistatic interaction between ERAP1 and HLA-B*27 in humans where loss of ERAP1 function reduces the risk of developing AxSpA. Preliminary studies indicate that ERAP1 deficiency and the attendant reduction in peptide supply in the endoplasmic reticulum has a paradoxical effect on the folding of HLA-B27, mitigating misfolding and some of its consequences and reducing the frequency of arthritis in rats. Possible mechanisms by which reduced misfolding impact arthritis are being investigated. Osteoblast Mineralization in Axial Spondyloarthritis Patient-derived skin fibroblasts are being used to generate induced pluripotent stem cell lines (iPSCs) that can be differentiated into osteoblasts to study aberrant mineralization processes. Preliminary studies have revealed that patient-derived cells mineralize to a greater extent than cells from healthy controls due in part to producing increased levels of an osteogenic cytokine that is targetable with existing biologics. Mechanisms underlying the increased expression of this cytokine, and a potential role for HLA-B*27 and other predisposing genes are being explored. In a separate project we are exploring effects of pro-osteogenic cytokines including the Th17 cytokine, IL-22, on osteoblast mineralization. While IL-22 has a minimal effect on mineralization when used alone, it causes a much more profound increase in mineralization when administered after cells are primed with IFNgamma and TNF. JAK Inhibitors in the Treatment of Juvenile Dermatomyositis We completed a compassionate use study of the Janus Kinase (JAK) 1/2 inhibitor baricitinib,in juvenile dermatomyositis (JDM). We demonstrated significant improvement using baracitinib in 4 JDM patients who had long-standing disease and were treatment-resistant (failed 3-6 immunomodulatory medications). Sustained effects of baracitinib have been observed after the initial study was completed. This work is expected to lead to a controlled trial of JAK inhibition in JDM with in-depth investigations of mechanisms.