LAUSR

Tumour necrosis factor inhibitors (TNFi) although effective in the treatment of rheumatoid arthritis (RA), show a variable response rate. Therefore, there is a need to identify treatment response predictors to inform therapy selection in order to practise precision medicine. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs that can alter gene expression by regulating messenger RNA translation. There is evidence for miRNA involvement in RA pathogenesis and they may serve as a useful biomarker of treatment response.To identify miRNAs associated with response to TNFi in RA.Biologic naïve patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), a prospective multi-center UK study investigating treatment response biomarkers to TNFi with a primary outcome measure of change in DAS28 scores. Patients were stratified into European League Against Rheumatism (EULAR) good or non-responders based on their 3 or 6-month DAS28-CRP score.Pre-treatment and 3-month post-treatment serum samples were substrates for miRNA profiling, which was conducted by FIRALIS using the HTG EdgeSeq miRNA whole transcriptome V2 targeted sequencing assay. Linear modelling using R package limma compared miRNA expression at (i) pre-treatment and at three-months, in EULAR good-responders and non-responders (ii) longitudinal change in expression from pre-treatment to three-months in EULAR good and non-responders.A literature search was conducted to identify miRNAs associated with RA as a diagnostic and/or treatment response predictor. Data on these miRNAs were extracted from the miRNAs identified in the serum samples. A correction for multiple testing was applied to statistical tests.A total of 54 patients were analysed; of these, 35 (65%) were female, median disease duration [inter-quartile range] was 6 years [2 – 14] (n=51), and 44/51 (86%) patients were on a concomitant disease modifying anti-rheumatic drug. Of the 54 patients, 39 (72%) were classified as EULAR good-responders and 15 (28%) as non-responders. 1880 miRNAs were detected in the serum samples. 64 miRNAs were identified to be associated with RA from the literature, of which, 26 were identified in the serum samples tested.No difference in pre-treatment or three-month miRNA levels was seen comparing EULAR good-responders and non-responders (FDR p<0.05). There was a significant differential expression of four miRNAs at 3-months in good-responders compared with pre-treatment levels; miR-125a-3p (downregulated, p-value 0.002), miR-149-3p (upregulated, p-value 0.004), miR-766-3p (downregulated, p-value 0.008), miR-146b-5p (upregulated, p-value 0.006). No significant differences were observed between 3-months and baseline in non-responders.Although no pre-treatment miRNAs were associated with TNFi response, changes in the levels of four miRNAs were detected at 3-months compared to baseline in EULAR good-responders. Future work involves validation of these samples in a larger patient cohort and analysing miRNA levels at 6 and 12 months. Replication and validation of these results in larger studies are required to analyse the role of miRNAs in stratifying EULAR good-responders from non-responders at three-months, and as treatment response predictors to TNFi in RA.Joint last-author: Dr. Darren PlantTrixy David: None declared, Nisha Nair: None declared, James Oliver: None declared, Eric Schordan: None declared, Hüseyin Firat: None declared, Kimme Hyrich Consultant of: consultancy/honoraria from AbbVie, Grant/research support from: Pfizer, UCB, BMS, Ann Morgan: None declared, Anthony G Wilson: None declared, John D Isaacs Speakers bureau: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Consultant of: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Grant/research support from: Pfizer, Darren Plant: None declared, Anne Barton: None declared