REsolving Seronegative and CheckpOint inhibitor-induced iNflammatory ArthriTis by synovial dEconstruction (RESONATE)

The immune system is highly effective at protecting us from harmful infection. It also helps prevent cancer by recognising and destroying cancer cells. As the immune system ages, however, it can itself cause disease which, when it affects the joints, is referred to as inflammatory arthritis. For those with rheumatoid arthritis whose blood tests are positive for markers called autoantibodies (seropositive RA), or those with an easily recognisable skin rash (psoriatic arthritis, PsA), it may be relatively simple for doctors to diagnose and treat these conditions. Indeed, the outlook for such patients has improved markedly thanks to a better understanding of underlying disease processes and the availability of drugs that target them. However, up to 500,000 UK adults suffer from other forms of "seronegative" inflammatory arthritis (SIA - so-called because their autoantibody tests are negative). These patients typically experience a long-term condition characterised by stiff, swollen joints, which is often disabling. Our understanding of SIA and how to treat it lags behind seropositive RA and PsA.

The development of a new class of drugs in cancer medicine, called immune checkpoint inhibitors (CPIs) could help us understand this problem in a new way. CPIs work by helping the immune system to attack and kill cancer cells, transforming the outlook for a rapidly increasing number of cancer patients. However, this strategy can also unleash the immune system on the body's harmless cells, and some CPI-treated patients develop inflammatory arthritis as a 'side effect.' In general, "CPI-induced arthritis" (CPIA) is remarkable for its similarity to SIA - and is just as difficult to manage. It affects around 8% of adults prescribed CPI therapy. We propose that by understanding this overlap between CPIA (precipitated by a known intervention) and SIA (whose cause is unknown) we will be able to find new ways to treat these diseases, either by repurposing treatments already used in other diseases or by identifying completely new approaches.

Researchers in Newcastle and Birmingham have worked together to collect and store blood and samples of joint lining (the synovium) from people with different forms of immune mediated inflammatory arthritis. Using samples from patients with SIA, CPIA, seropositive RA and PsA, we will employ recently developed technologies to extract highly detailed information about constituent cells in each condition, and how they interact with one another to drive inflammatory disease. Using computational approaches to compare them in collaboration with colleagues at the University of Glasgow and GSK, we will seek to identify the particular pathological features of SIA that explain why it looks so similar to CPI-induced arthritis in the clinic. The information gained should (i) help identify future treatment approaches for both conditions and (ii) help us develop blood tests to predict those individuals most likely to benefit from them. As a preliminary test of such treatments, we will explore their ability to disrupt the unwanted behavior of implicated disease-causing cells in the laboratory. In parallel, we will work with our network of academic and pharmaceutical collaborators to design trials that test them in the clinic

Over 1.5M UK adults suffer from immune mediated inflammatory arthritis of the peripheral joints. Anti-modified peptide antibody-positive rheumatoid arthritis (AMPA+ RA) and psoriatic arthritis (PsA) have emerged as discrete "endotypes" at poles of this disease spectrum - for which targeted therapies reflect growing understanding of respective pathologies. Between them lie a poorly served group of patients with seronegative inflammatory arthritis (SIA), who lack both detectable circulating autoantibodies and overt clinical features of psoriasis/ spondyloarthropathy. Their clinical phenotype bears remarkable similarity to an emergent, nosocomial arthritis seen in oncology patient recipients of the checkpoint inhibitor (CPI) class of drugs, that block co-inhibitory immune modulation to enhance tumour cytotoxicity. We hypothesise that cellular and/or molecular characteristics of synovitis shared between SIA and CPI-induced arthritis discriminate it from that seen in AMPA+ RA and/or PsA. We will:

-Undertake a comparative analysis of disaggregated synovial tissue and paired peripheral blood mononuclear cells (PBMCs) from inception cohorts of arthritis patients and CPI recipients using single cell transcriptomics.

-In respect of highlighted cell phenotypes, contextualize our findings and those of others by analyzing paired tissue sections in comparator groups of interest using spatial transcriptomics (GeoMx) and imaging mass cytometry (Hyperion).

- Building on emergent data, propose and prospectively appraise putative peripheral blood flow cytometric biomarkers in an inception cohort of CPI recipients as means to predict CPI-A, and undertake in vitro mechanistic studies to validate potential therapeutic strategies.