Increased Plasma Microbial tDR ‐1 in At‐Risk Individuals Is Associated With Decreased Conversion to Clinical Rheumatoid Arthritis and Reduces an In Vitro Macrophage Type 1 Interferon Response

Objective Microbial small RNAs can regulate human genes. Higher plasma concentrations of microbial transfer RNA (tRNA)‐derived RNA‐1 (tDR‐1) were previously associated with lower rheumatoid arthritis (RA) disease activity. This study examined whether tDR‐1 concentrations differ in anticyclic citrullinated peptide‐3 positive (CCP3+) at‐risk individuals (ARI), based on who later develops clinical RA, or discriminate later conversion status beyond established risk factors and if tDR‐1 has in vitro effects. Methods Plasma tDR‐1 concentrations were measured in CCP3+ ARI. Group differences in log‐transformed tDR‐1 were assessed by lognormal Welch's t ‐test and logistic regression. Area under the receiver operating characteristic curve (AUROC) was used to evaluate discriminatory ability. Human THP‐1 monocyte‐derived macrophages were treated with tDR‐1 versus scramble control, and gene expression was assessed by NanoString Immunology panel. Results Among 60 CCP3+ ARI, 25 later developed clinical RA (“converters”) over a mean of 2.2 years, whereas 35 did not (“nonconverters”) over a mean of 5.3 years. Baseline plasma tDR‐1 concentrations were significantly higher (5.4‐fold) in nonconverters versus converters, even after adjustment for additional RA risk factors (shared epitope, smoking, rheumatoid factor) ( P = 5.1 × 10 −4 ). The AUROC improved from 0.722 for these risk factors alone to 0.902 with the addition of tDR‐1 ( P = 0.003). In vitro, tDR‐1 significantly down‐regulated many type 1 interferon (IFN) response genes in THP‐1 cells. Conclusion Higher plasma tDR‐1 concentrations were associated with nonconversion to clinical RA in CCP3+ ARI. tDR‐1's reducing type 1 IFN response gene expression suggests a potential mechanism by which microbes and tDR‐1 could affect RA development. image