ABSTRACT
Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.
Subject(s)
Arthritis, Psoriatic/immunology , CD8-Positive T-Lymphocytes/immunology , Clonal Selection, Antigen-Mediated , Receptors, Lymphocyte Homing/metabolism , Synovial Fluid/immunology , Arthritis, Psoriatic/blood , CD8-Positive T-Lymphocytes/metabolism , Gene Expression Profiling , Humans , Immunologic Memory , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Chemokine/metabolism , Receptors, Lymphocyte Homing/genetics , Single-Cell Analysis , Synovial Membrane/immunologyABSTRACT
PURPOSE OF REVIEW: Axial spondyloarthritis remains an area of significant unmet clinical need with only two immune pathways currently targeted by licenced therapies compared to other immune-mediated inflammatory joint disorders such as rheumatoid arthritis where a multitude of therapeutic options are available. This review will look at emerging therapeutic targets in axial spondyloarthritis beyond the neutralisation of IL-17A and TNF by monoclonal antibodies. RECENT FINDINGS: Several promising targets are in various stages of pre-clinical and clinical development in axial spondyloarthritis. These include small molecule approaches to target transcription factors, epigenetic modification and intracellular modulation of cytokine signalling by kinase inhibition. GM-CSF has also emerged as a potential driver of inflammation. SUMMARY: A number of novel and promising therapeutic options are in various stages of development in axial spondyloarthritis. The Janus kinase inhibitors have shown great promise in other immune-mediated inflammatory disorders and will be an exciting addition to the axial spondyloarthritis field as the first oral disease-modifying agents. GM-CSF blockade also shows great promise since antibodies for neutralising this cytokine are safe in patients and have shown efficacy in other immune-mediated inflammatory diseases.
