Investigating Oncostatin M as a Mediator of Seronegative Inflammatory Arthritis.

Unmet need. Seronegative inflammatory arthritis (SIA) describes a spectrum of immune-mediated peripheral joint disease in which circulating autoantibodies are absent. Affecting about 300,000 UK adults with conditions including psoriatic arthritis (PsA), rheumatoid arthritis (RA) and undifferentiated arthritis (UA), effective treatment strategies for SIA remain a major unmet need.

Rationale. Oncostatin M (OSM) is an IL-6-family cytokine that signals via gp130-OSMR? or gp130-LIFR? heterodimers, variously utilising Jak1/2-STAT3/5, PI3K-Akt and MAPK signalling machinery in different cell types1. An anti-OSM IgG1 monoclonal antibody GSK2330811 is in development2. Increased expression of OSM is a recognised feature of human inflammatory arthritis3, and its over-expression in mice leads to synovial hyperplasia4. Compelling evidence also exists for OSM's role in the pathogenesis of inflammatory bowel disease (IBD)5 and skin psoriasis6,7 - both conditions that frequently co-present with SIA. Recently, dysregulated OSM signalling was further shown to define an IBD endotype resistant to existing therapies including anti-TNF5. Optimal assessment of this pathway's therapeutic tractability in SIA requires a comprehensive understanding of its activation in treatment-naïve patients, including its relationship with responses to subsequent routine therapeutic intervention. Existing biological samples from our early arthritis cohorts afford us a rare opportunity to address this.
Key objectives. In a 1 year pilot study we will (a) measure OSM signalling biomarkers, including a recently characterised OSM-associated gene expression module5, in the synovial tissue and circulation of untreated SIA patients compared with seropositive RA and osteoarthritis (OA) controls, and (b) explore their association with subsequent therapeutic responsiveness.
Plan. We will make use of samples from 20 treatment-naïve SIA patients enrolled into the Newcastle Early Arthritis Cohort (NEAC), in whom formalin-fixed, paraffin-embedded (FFPE) synovial tissue is available for analysis. Tissue from 20 untreated early seropositive RA patients matched for acute phase response, as well as 10 OA patients, will also be available for comparison. A substantial proportion of the study cohort is already recruited at the time of proposal submission (Table 1) and the remainder will be enrolled prior to the project start date. Baseline clinical parameters, therapeutic interventions and prospective disease activity data are recorded for all patients and therapeutic response to standard treatment will be determined at 4 months, anticipating 60% response rate in SIA patients (Table 1). FFPE tissue will undergo (i) morphological analysis (H+E staining and grading according to established criteria8), (ii) immunofluorescence staining (stromal and lymphocyte markers, OSMR?, LIFR?, gp130) and (iii) RNA extraction using (RNeasy FFPE kit) for subsequent expression profiling by next generation RNA-Seq. Utilising paired banked sera, TNF, soluble gp130 and OSM will be measured using validated electro chemo-luminescence assays (MSD).
For parallel analyses exploring the value of blood parameters in predicting therapeutic responsiveness at 4-6 months, peripheral blood genome-wide expression data will be interrogated in two independently recruited, treatment-naïve inflammatory arthritis patient cohorts; namely, the NEAC cohort (Table 2) and the Scottish Early Rheumatoid Arthritis (SERA) cohort9 - the latter also affording enhanced power for comparisons between seronegative and seropositive RA.
Analysis. The primary analysis will determine whether expression of OSM/OSMR and/or a previously defined 21 gene cytokine expression "module"6 in SIA synovial tissue (i) predicts DMARD response at 4 months, and (ii) differs significantly in seropositive RA and OA tissue. Based on Ref 5 (Figure 2f) n=20 will afford sufficient power to ascertain differential OSM expression in responder versus non-responder SIA tissue. Exploratory analyses will focus on tissue morphology and histological parameters for the same purpose, the extent to which paired serum OSM correlates with TNF, and whether transcriptional evidence of OSM versus TNF signalling in the periphery associates with autoantibody-defined pathotype and/or predicts subsequent therapeutic responsiveness..