OP0217 INVOLVEMENT OF LARGE JOINTS AT DISEASE PRESENTATION IS ASSOCIATED WITH DIVERSE HISTOPATHOLOGICAL FEATURES AND CLINICAL OUTCOMES IN EARLY RHEUMATOID ARTHRITIS
Authors: F. Rivellese, F. Humby, G. Lliso Ribera, A. Nerviani, E. Sciacca, G. Giorli, R. Hands, L. Fossati-Jimack, G. Thorborn, M. Lewis, C. Pitzalis
Journal: Annals of the Rheumatic Diseases (2020)

Background: The involvement of large joints at disease presentation in early Rheumatoid Arthritis (RA) has been associated with severe disease activity. At the same time, the clinical heterogeneity of RA is known to be mirrored by heterogeneity of synovial inflammation, with specific histological patterns (pathotypes) associated with treatment response and disease progression. However, it is not known whether joint size is associated with specific pathotypes. Objectives: To analyse histopathological features of synovial biopsies from joints of different sizes and establish the relationship with clinical outcomes in patients with early RA. Methods: 167 patients with early (&lt;1 year) treatment-naïve RA, fulfilling the 2010 RA criteria and recruited at Barts Health NHS Trust, underwent US-guided synovial biopsy of the most inflamed joint, either large (knee), medium (e.g. wrist, ankle, elbow) or small (MCPs, MTPs), before starting treatment with csDMARDS with a treat to target approach. Upon SQ scoring (0-4) of immune cell infiltration, tissues were classified into lympho-myeloid, diffuse-myeloid and pauci-immune pathotypes. Synovial samples from 111 patients underwent RNA-seq. Results: The majority of synovial biopsies were performed on medium and small joints (60.6% and 19.4%) as compared to 21.3% in large joints (Table 1). At baseline, patients who underwent large joint biopsy showed significantly higher levels of inflammation (CRP 27.9±32.4 large, 20.7±26.9 medium, 10.4±9.8 small, p=0.007) and higher HAQ (1.8 ± 0.7 large, 1.4 ± 0.8 medium, 1.2 ±0.9 small, p=0.012), with no differences in DAS28. Significantly higher inflammatory scores and higher proportion of lympho-myeloid pathotype were observed in large joints (Table 1 and Figure 1). 6 months after treat-to-target treatment with csDMARDs, large joints patients had significantly higher HAQ and lower response (RR for low disease activity in large vs medium joints 0.5, 95%CI 0.2-0.9, p=0.03). Finally, differentially expressed genes by RNA-seq showed segregation according to joint size (Figure 2), with upregulation of genes of the Homeobox transcription factors family in large joints. Table 1. EULAR 2010 RA (n=167) Large joints# 33 (19.4%) Medium joints# 100 (60.6%) Small Joints# 34 (20%) P* Clinical features ESR mm/h, mean (SD) 48.2 (31.5) 39.6 (30.8) 29.2 (17.3) ns CRP mg/L, mean (SD) 27.9 (32.4) 20.7 (26.9) 10.4 (9.8) 0.007 DAS28 , mean (SD) 6 (1.2) 5.7 (1.4) 5.7 (1.5) ns HAQ , mean (SD) 1.8 (0.7) 1.4 (0.8) 1.2 (0.9) 0.012 ACPA-positive , % 70.9% 77.3% 83.9% ns RF-positive, % 71.9% 74.2% 80.6% ns Histology Inflammatory score, median IQR) 5 (3) 4 (4) 2 (2.75) &lt;0.001 Pathotype, % Ungraded 6.1% 7.8% 2.9% 0.014 Fibroid 6.1% 24.3% 32.3% Myeloid 30.3% 28.1% 47.1% Lympho-myeloid 57.6% 39.8% 17.6% Clinical outcomes at 6 months DAS28 6m, mean (SD) 4.2 (1.8) 3.4 (1.9) 3.7 (1.5) ns HAQ 6m, mean (SD) 1.2 (0.8) 0.8 (0.8) 0.8 (0.8) 0.012 DAS28 6m &lt;3.2, % 23.3% 48.8% 37.9% 0.04 #Large joints: knees; Medium joints: wrists, ankle, elbows; Small joints: MCPs, MTPs, PIPs; * Chi-squared or Kruskal–Wallis as appropriate; Conclusion: Synovial biopsy of large joints as the most inflamed joints at disease presentation identified patients with early RA with specific histopathological features and clinical outcomes. Together with clustering of differentially expressed genes according to joint size, this suggests that the involvement of different joint compartments in early RA contributes to disease heterogeneity with potential physiopathological and clinical implications. References: [1]Humby et al Ann Rheum Dis. 2019 Jun;78(6):761-772 [2]Lewis et al Cell Rep. 2019 Aug 27;28(9):2455-2470.e5 [3]Linn-Rasker SP et al Ann Rheum Dis. 2007 May;66(5):646-50 Acknowledgments: PEAC http://www.peac-mrc.mds.qmul.ac.uk MRC grant 36661 &amp; ARUK Grant 20022 F. Rivellese NIHR Fellowship TRF-2018-11-ST2-002 Disclosure of Interests: None declared