Pathogenic Mechanisms in Spondyloarthritis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Children with SpA and axial involvement frequently fail to meet adult classification criteria, and can be excluded from adult trials. New drugs for adults with AxSpA often remain unstudied in children because of waivers from regulatory agencies. Thus, children with SpA 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 and studied in a similar manner. We have worked with colleagues to raise awareness of these issues and continue to advocate for more extrapolation of results from adult trials, as well as more safety studies in children. Many common genetic variants discovered in genome-wide association studies contribute to the risk of developing AxSpA. Disease mechanisms in AxSpA, and the role of common genetic variants, remain poorly understood. We have effectively used a rodent model of HLA-B*27-induced experimental SpA to investigate disease mechanisms including gene-gene interactions and continue to examine other pathways in SpA pathogenesis using induced pluripotent stem cells (iPSCs) derived from patient cells. ERAP1 variants associated with risk or protection from AxSpA operate predominantly in individuals carrying HLA-B*27, thus indicating a gene-gene or epistatic interaction. We addressed the mechanism of this interaction in HLA-B*27 transgenic rats, demonstrating that eliminating ERAP1 expression protects them from arthritis. This mimics what is observed in humans, where variants that cause loss-of-function ERAP1 or reduced expression also reduce the risk of arthritis. In rats ERAP1-deficiency reduced aberrant properties of HLA-B*27 and improved its ability to fold and exit the endoplasmic reticulum (ER), implicating misfolding in the generation of arthritic disease. This work opens new avenues of investigation in AxSpA and indicates that inhibiting ERAP1 might be beneficial therapeutically. A potential mechanism by which HLA-B*27 misfolding could lead to inflammation is through activation of the cellular unfolded protein response (UPR) and upregulation of the transcription factor CHOP. CHOP promotes IL-23 production which may drive the accumulation and activation of IL-23-responsive, CD4+ Th17 T cells that produce pro-inflammatory cytokines such as IL-17A. We generated CHOP-deficient rats to ask whether features of experimental SpA in HLA-B*27-expressing rodents were mitigated. While CHOP-deficient cells failed to exhibit super-induction of the Il23a, eliminating CHOP did not diminish colon inflammation, and in fact made the inflammation somewhat worse. Thus, while other studies such as the role of ERAP1 in experimental SpA continue to implicate aberrant features of HLA-B*27 in disease, there is no clear link between HLA-B*27 misfolding and CHOP-mediated IL-23 overproduction. Genetic Contributions to Early Onset Axial Spondyloarthritis We evaluate children with early onset AxSpA in the NIH Clinical Center. Using a trio-based approach and whole exome/genome sequencing, we have identified several rare genetic variants or de novo mutations that may contribute to disease onset and phenotype. Progress was slowed during the pandemic because of restrictions on patient/family flow in the Clinical Center, but work has resumed. Laboratory-based studies support the functional impact of several of these variants on relevant pathways in SpA pathogenesis. Osteoblast Mineralization in Axial Spondyloarthritis We are modeling bone formation in AxSpA using patient-derived induced pluripotent stem cells (iPSCs). IPSCs can be differentiated into mesenchymal cells (MSCs) and then osteoblasts to study aberrant mineralization processes. Preliminary studies reveal that patient derived cells have an increased capacity to mineralize compared to healthy controls. This is due in part to overexpression 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.