Background/Purpose: Despite valuable improvements in long-term clinical outcomes, a significant portion of rheumatoid arthritis (RA) patients still do not adequately respond to available treatments, and early prognostic biomarkers of response are missing. Single-cell transcriptomic studies on RA synovial tissue (ST) revealed that MerTK is highly expressed in “anti-inflammatory” macrophages [1]. Moreover, synovial macrophages isolated from RA patients in remission show a typical CD206+/MerTK+ signature [2]. Finally, monocyte-derived macrophages from RA patients treated with TNF-inhibitors (TNF-i) up-regulate MerTK on their surface.
In this study, we aim at i) assessing the modulation of synovial tissue MerTK+ macrophages upon treatment with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and ii) evaluating the relationship between baseline MerTK synovial gene expression and future response to TNFi.

Methods: Patients with early (< 12 months) treatment-naïve RA (as per ACR/EULAR 2010 criteria) underwent a US-guided synovial biopsy of an inflamed peripheral joint at baseline and a second biopsy of the same joint six months after starting treatment with single or multiple csDMARDs. ST was collected and used for histology and RNA extraction. ST (n=15) was stained for CD68, MerTK and CD206 by immunofluorescence using a tyramide amplification signal system. The percentage of single- (MerTK+ or CD206+) and double-positive (CD206+MerTK+) CD68+ macrophages was quantified by digital image analysis (Image J). Gene expression analysis was performed on RNA sequences of 22 baseline ST-samples (treatment-naïve).

Results: Before treatment, the percentage of MerTK+CD206+ macrophages was significantly higher in RA patients with low (DAS28< 3.2) versus high (DAS28 >5.1) disease activity (24.5±20.1 versus 4.8±4.8, p< 0.05). No differences were detected 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. Patients (n=5) achieving remission (DAS< 2.6) at 6-months significantly increased the number of MerTK+ macrophages from baseline in comparison with patients (n=5) who were still active post-treatment (23.6±23.8 to 55.5±15.4, p< 0.05 versus 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 who subsequently responded to TNFi (n=14, good/moderate EULAR) in comparison with those who did not respond (n=8) (p = 0.003).

Conclusion: Our whole-tissue expression data further corroborate the hypothesis that a selective expansion of the MerTK+ macrophage subset defines patients achieving remission. Moreover, the up-regulation of the MerTK gene at baseline in patients future responders to TNFi suggest that MerTK is involved in modulating synovial inflammatory responses and might be exploited as a therapeutic target in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mertk-synovial-expression-correlates-with-disease-activity-and-treatment-response-in-rheumatoid-arthritis-patients/