Objectives Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased.

Methods ERE expression in DMARD naïve eRA whole blood (LINE1; RT-PCR) and bulk synovial tissue (LTR5, LINE1, SINE; Nanostring) was examined alongside IFN-α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (PsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data was re-interrogated to identify repeat elements, and associations explored.

Results There was significant co-expression of all ERE classes and IFNA in eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN-α protein (p=0.018) and anti-CCP titres (p<0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with PsA, with ERE regulation by SAMDH1 implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B cells, T cells and fibroblasts), ERE expression associated with increased IFN-I signalling (p<0.001).

Conclusions Peripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

JDI disclosures speaker/consulting fees from AbbVie, AstraZeneca, Galapagos and Participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly. AGP discloses research funding from GSK, Pfizer, Gilead, and consulting fees from Inflection Biosciences. FAHC discloses speaker fees from AstraZeneca. The remaining authors have no competing interests.

This work was funded The Medical Research Council; Academy of Medical Sciences; JGW Patterson Foundation and British Society of Rheumatology. Experimental work at Newcastle University was additionally supported by the Medical Research Council in collaboration with GSK (MR/S50239X/1). Views expressed are the authors and not necessarily those of the National Health Service, the National Institute of Health and Care Research or the Department of Health.

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For the early disease data all patients provided written, informed consent to participate in the study, which was approved by the Northeast Newcastle and North Tyneside 2 Research Ethics Committee (12/NE/0251).

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