OP0120 BASELINE CELLULAR AND MOLECULAR CHARACTERISTICS OF SYNOVIAL TISSUE AND RELATION WITH TNFI RESPONSE. RESULTS FROM THE PATHOBIOLOGY OF THE EARLY ARTHRITIS COHORT (PEAC)
Authors: Gloria Lliso Ribera, Frances Humby, Alessandra Nerviani, Myles Lewis, Stephen Kelly, Michele Bombardieri, Katriona Goldmann, Rebecca Hands, Chris Buckley, Peter C. Taylor, Iain B Mcinnes, Costantino Pitzalis
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Despite early intervention with disease modifying therapy a high percentage of patients (∼30%) fail to respond and require escalation to advanced therapies such as TNFi, with no available biomarkers to predict response. Whether synovial signatures predicting subsequent response to TNFi therapy can be identified at disease onset remains an unanswered question although critical for long term prevention of disease progression and overall health economic impact. <h3>Objectives</h3> The aim of this study was to evaluate in a cohort of treatment naïve early RA patients, whether baseline synovial cellular and molecular signatures predict subsequent response or not to anti-TNF therapy. <h3>Methods</h3> A total of 186 consecutive DMARD naïve inflammatory arthritis patients (disease duration &lt;1 year) recruited as part of the multicentre PEAC study at Barts Health NHS Trust were evaluated. After 12 months 35 patients commenced therapy with a TNFi (DAS28&gt;5.1, failed 2 x cDMARDs as per UK NICE guidelines). EULAR response (DAS28 and DAS improvement from baseline) was calculated 12 months after TNFi was initiated. All patients underwent an US guided baseline synovial biopsy of a clinically active joint along with collection of clinical characteristics. Following H&amp;E staining, sections underwent immunohistochemical staining and semi-quantitative scoring (0-4) to determine the degree of CD20+Bcells, CD3+T cells, CD68+ lining (l) and sublining (sl) macrophage and CD138+ plasma cell infiltration. Sections were categorised into three pathotypes: (i) Fibroid: (CD68 SL&lt;2 and or CD3, CD20, CD138&lt;1), (ii) Myeloid: (CD68SL&gt;2, CD20&lt;1 and or CD3&gt;1) and (iii) Lymphoid: (grade 2-3 CD20+ aggregates, CD20&gt;2). Synovial gene expression was evaluated with Nanostring and RNA sequencing. <h3>Results</h3> 12 months after TNFi was initiated 17/35 (48%) patients responded to therapy (TNFi good EULAR response) and 18/35 (52%) had a moderate or non-response to TNFi. Baseline demographic or US characteristics did not differentiate between the 2 groups. Although we saw no significant differences between groups there was a trend for higher levels of B (CD20+) and T (CD3+) cells, sub-lining macrophages (CD68+) and plasma cells (CD138+) in the TNFi response group. The cohort was segregated by pathotype and each clinical parameter was compared from baseline to 12months. Interestingly, we observed a significant reduction of levels of CRP, VAS and DAS28 and number of tender and swollen joints in those patients with Lymphoid and Myeloid pathotype (p&lt;0.05), but not in those with Fibroid pathotype (Figure 1). We also evaluated gene expression (using Nanostring and RNA-sequencing) and observed increased expression of genes related to macrophages, plasma cells and B/T regulatory cells expression/activation and/or stimulation at baseline in patients who responded to TNFi. <h3>Conclusion</h3> This study demonstrates first evidence of potential novel signatures/biomarkers of TNFi response in treatment naïve early RA. Clinical or US assessment cannot discriminate between responders to TNFi. Lymphoid and Myeloid pathotypes associated with significant falls in clinical outcome. Finally, molecular signatures including differential upregulation of T cells, B cells and macrophage associated genes are associated with good response to TNFi therapy. <h3> Disclosure of Interests</h3> Gloria Lliso Ribera: None declared, Frances Humby: None declared, Alessandra Nerviani: None declared, Myles Lewis Grant/research support from: Celgene, Stephen Kelly: None declared, Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, Katriona Goldmann: None declared, Rebecca Hands: None declared, Chris Buckley Consultant for: GlaxoSmithKline, Peter C. Taylor Grant/research support from: Celgene, Galapagos, Eli Lilly, UCB, Consultant for: AbbVie, Galapagos, Gilead, Eli Lilly, Pfizer Inc, Iain B McInnes: None declared, Costantino Pitzalis Grant/research support from: Celgene