THU0082 MERTK SYNOVIAL EXPRESSION CORRELATES WITH TREATMENT RESPONSE IN RHEUMATOID ARTHRITIS
Authors: A. Nerviani, M. A. Boutet, G. M. Ghirardi, G. Lliso Ribera, F. Rivellese, M. Lewis, M. Bombardieri, F. Humby, C. Pitzalis
Journal: Annals of the Rheumatic Diseases (2020)

Background: Despite substantial improvements in long-term clinical outcomes, a significant proportion of rheumatoid arthritis (RA) patients still fail to respond to treatment adequately, and early prognostic biomarkers of response are missing. Single-cell transcriptomic studies on RA synovial tissue (ST) have shown that MerTK is highly expressed in “anti-inflammatory” macrophages [1]. It has also been suggested that synovial macrophages isolated from RA patients in remission are characterised by a CD206+/MerTK+ signature [2]. Finally, monocyte-derived macrophages from RA patients treated with TNF-inhibitors (TNF-i) up-regulate MerTK. Objectives: To assess i) the modulation of synovial tissue MerTK+ macrophages upon treatment with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and ii) the relationship between baseline MerTK gene expression and response to TNFi. Methods: ST was obtained by US-guided synovial biopsies of an inflamed peripheral joint in patients with early (&lt;12 months) treatment-naïve RA (as per ACR/EULAR 2010 criteria). A second biopsy of the same joint was repeated six months after starting treatment with single or multiple csDMARDs. ST (n=15) was stained for CD68, MerTK and CD206 by immunofluorescence using a tyramide amplification signal system. Quantification of the percentage of single- (MerTK+ or CD206+) and double-positive (CD206+MerTK+) CD68+ macrophages was obtained by digital image analysis (Image J). Gene expression analysis was performed on RNA sequences of 22 baseline ST samples (treatment-naïve). Results: Before any treatment intervention, the percentage of MerTK+CD206+ macrophages was significantly higher in RA patients with low (DAS28&lt;3.2) versus high (DAS28&gt;5.1) disease activity (24.5±20.1 versus 4.8±4.8, p&lt;0.05). There were no differences in the relative number of MerTK+ or CD206+ or MerTK+CD206+ macrophages at baseline in relationship with the clinical response to csDMARDs at 6-months. On the other hand, patients (n=5) achieving remission (DAS&lt;2.6) upon receiving csDMARDs significantly increased the number of MerTK+ macrophages from pre- to six-months post-treatment (23.6±23.8 to 55.5±15.4, p&lt;0.05) in comparison with patients (n=5) who were still active after treatment (18±15.6 to 30.4±11.17, p=ns). MerTK synovial gene expression at baseline (i.e., in newly diagnosed treatment-naïve RA patients) was significantly higher in patients subsequently treated with TNFi and achieving a good/moderate EULAR response at 12 months in comparison with those who did not respond (n=14, n=8, p adjusted 0.003). Conclusion: Our whole-tissue protein expression data further support the hypothesis that a selective expansion of the MerTK+ macrophage subset characterise patients achieving remission. Moreover, the pre-treatment up-regulation of the MerTK gene in future responders to TNFi suggest that MerTK is implicated in modulating synovial inflammatory responses and may be exploited as a therapeutic target in RA. References: [1]F. Zhang et al, Nature Immunology, vol. 20, no. 7, pp. 928–942, 2019. [2]S. R. Finlay at al, Annals of the Rheumatic Diseases, vol. 77, Supplement 2, pp. 183–183, 2018. [3]Y. Degboé et al, Frontiers in Immunology, vol. 10, p. 3, 2019. Acknowledgments: Versus Arthritis Disclosure of Interests: None declared