Pathogenic Mechanisms in Spondyloarthritis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Treatment of Spondyloarthritis (SpA) in Children Children with ERA with axial involvement frequently fail to meet classification criteria for adult AxSpA (or ankylosing spondylitis), and for this and other reasons are often excluded from adult trials. Furthermore, due in part to waivers from regulatory agencies, newly approved drugs are often not studied in children in a timely fashion. Thus children, have not been afforded the same disease-modifying treatments that are available for adults. We have emphasized in the literature, the considerable evidence indicating that ERA, particularly when there is axial involvement but also with peripheral arthritis, exists on a continuum with adult SpA and should be treated in the same manner. Genetic predisposition, pathogenic mechanisms, and clinical manifestations of SpA are largely overlapping in children and adults. We have worked with colleagues to raise awareness of these issues and advocated for more extrapolation of results from adult trials, as well as more safety studies in children. Epistasis Between ERAP1 and HLA-B*27 ERAP1 (endoplasmic reticulum aminopeptidase 1) variants are associated with risk or protection from AxSpA in individuals carrying HLA-B*27. We generated ERAP1 knockout rats to address the mechanism of this epistatic interaction and found that ERAP1-deficient HLA-B*27 transgenic rats are protected from arthritis. Thus, the animal model mimics what is seen in humans, where variants of ERAP1 that lower its activity also reduce the risk of arthritis in HLA-B*27 carriers. Surprisingly, ERAP1-deficiency reduced HLA-B*27 misfolding and improved the egress of HLA-B*27 heavy chains from the endoplasmic reticulum (ER), thus implicating misfolding in the generation of arthritic disease. This unexpected result is paradoxical since the main function of ERAP1 is to optimize the supply of peptides, which helps most HLA class I proteins to fold and exit the ER. This work opens new avenues of investigation in AxSpA and suggests the ERAP1 inhibition might be of therapeutic benefit. Genetic Contributions to Early Onset Axial Spondyloarthritis We continue to evaluate children with early onset AxSpA in the NIH Clinical Center. Using a trio-based approach and whole exome/genome sequencing, we are looking for rare genetic variants or de novo mutations that may contribute to disease onset and phenotype. Several candidate genes have been identified, but progress was slowed by COVID-related restrictions on patients and family members being seen in the Clinical Center. The project continues and enrollment has picked up considerably in the last year. Osteoblast Mineralization in Axial Spondyloarthritis We are modeling one aspect of bone formation in AxSpA using patient-derived induced pluripotent stem cells (iPSCs) that are produced from skin fibroblasts. IPSCs can be differentiated into mesenchymal cells (MSCs) and then osteoblasts to study aberrant mineralization processes. Preliminary studies reveal increased mineralization capacity in patient-derived cells compared to healthy controls. This is due in part to increased expression of an osteogenic cytokine that is targetable with existing biologics, but not those currently used to treat AxSpA. Mechanisms underlying this effect, and the role of HLA-B*27 and other predisposing genes are being explored. We are also exploring the role of pro-osteogenic cytokines such as IL-22, on osteoblast mineralization. While IL-22 has a minimal effect on mineralization when used alone, its effect on mineralization is magnified when administered after cells are primed with IFN-gamma and TNF.