Pathogenic Mechanisms in Spondyloarthritis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

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Abstract

Differences in presentation of SpA in children and adults have necessitated different sets of classification criteria. Children with axial involvement frequently fail to meet adult classification criteria for AxSpA because of a lack of inflammatory back pain when the disease begins. This can delay institution of appropriate therapy that might otherwise reduce morbidity and improve long-term outcomes. In a large collaboration, we developed classification criteria for axial disease in children with spondyloarthritis (JAxSpA). In children with JSpA and when axial disease is suspected, evidence for structural lesions and/or bone marrow edema on magnetic resonance imaging (MRI) in and around the sacroiliac joint needs to be present to meet AxJSpA classification criteria. These criteria have been validated and can be used to identify participants for research studies, which will accelerate therapeutic development. Detecting and defining axial involvement JSpA remains a challenge. We demonstrated the importance of MRI in detecting axial disease in an international study of 303 of JSpA patients. MRI findings influenced clinical data in close to 40% of the cases, either confirming or refuting the presence of axial inflammation. We demonstrated that MRI improves the confidence of expert assessment of axial disease, underscoring the integral role of this imaging modality in JSpA. We found that youth who meet the new AxJSpA criteria do not always fulfill criteria previously developed by the Paediatric Rheumatology International Trials Organization (PRINTO) aimed at harmonizing adult and pediatric classification of juvenile idiopathic arthritis (JIA) including JSpA. The main reasons for not fulfilling PRINTO criteria were the absence of peripheral manifestations like peripheral arthritis and enthesitis, and the presence of HLA-B27. We reviewed recent developments in the field of HLA-B*27 research. There are three main lines of evidence that HLA-B*27 directly impacts the development or severity of SpA. T cell receptor (TCR) sequencing and identification of peptides targeted by expanded TCR clones has reopened a promising line of investigation. In addition, there is evidence that depleting these T cells that target HLA-B*27 may be efficacious in treating AxSpA. We obtained supplementary funding from the Office of Autoimmune Disease Research (OADR) to sequence TCRs in our large cohort of JSpA, JAxSpA, and adult subjects to determine whether T cell clonal expansions are present in early, pediatric disease, and whether there are additional clonal expansions yet to be discovered. In addition to its role presenting antigenic peptides, HLA-B*27 misfolding has been implicated in aberrant bone formation by promoting osteogenic mineralization by osteoblasts derived from mesenchymal stromal cells (MSCs). Aberrant forms of HLA-B*27 on the cell surface are also implicated in triggering IL-17 production from CD4+ Th 17 T cells. Importantly, we demonstrated that HLA-B*27 misfolding does not lead to gut inflammation via activation of the unfolded protein response (UPR) and upregulation of IL-23. This work, accomplished using an animal model that recapitulates human disease, advances the field significantly reducing the need for additional studies in human subjects.