Background/Purpose: Neuropathic pain is one of the most common clinical characteristics of rheumatoid arthritis (RA). It often does not subside with the use of DMARD, which greatly impacts the quality of life of RA patients. Overall, RA etiology is mediated by a complex interplay between genetic and environmental factors leading to epigenetic deregulation and data suggests this is also the case with neuropathic pain. One of the epigenetic marks altered in RA pathogenesis is the deregulation of microRNAs (miRNAs) levels, which are non-coding RNAs that negatively regulate gene expression. Recent studies in rodents report an association between lower levels of some miRNAs and negative regulation of genes that are involved in neuropathic pain mechanisms. However, little is known about RA-related neuropathic pain and miRNAs in humans. Here, we conducted a pilot study to identify miRNAs associated with neuropathic pain in RA patients. We further use bioinformatic tools to identify the molecular pathways associated with the deregulation of those miRNAs

Methods: We recruited 27 RA patients, and collected serum and clinical, demographic and lifestyle data. We isolated exosomes from their serum, to extract and determine levels of 800 miRNAs using Nanostring nCounter miRNA expression panels. For analysis, we use ID pain as a measure of neuropathic pain, and categorize participants in two groups: high pain (HP, ID pain≥4) and low pain (LP, ID pain< 4) considering the median level of the study population. Because of the small number of samples, we applied the following criteria for the selection of neuropathic pain-related miRNAs: a magnitude difference between groups within the top 10%, a fold change in the top 50% and > 75% of the sample with change in the same direction. To predict possible pain signaling pathways associated with the identified miRNAs, we used miRDB, miRWalk and TargetScan databases to identify the corresponding gene targets. We followed by using DIANA and DAVID softwares to determine the pathways most likely affected by the newly identified miRNAs. Pathways identified by both softwares with Benjamini values (Q) below 0.05 were considered to be highly likely to be affected by the deregulated miRNAs.

Results: We identified four miRNAs to be associated with RA-related neuropathic pain in this population. Levels were lower in the HP than the LP group for all miRNAs (miR-3151-5p LP=36.56±7.03 vs HP=27.71±26.21, (p=0.0096), mir-1307-5p LP=37.87±15.02 vs HP=24.09±18.82, (p=0.0173), mir-656-3p LP=35.15±11.24 vs HP=23.44±16.87, (p=0.0239), and miR-520c-3p LP= 30.98 SD±6.59 vs HP=20.48±18.55, (p=0.0126)). We also identified 56 pathways, which we predicted to be deregulated as a result of changes in these miRNA. Two of the neuropathic pain-relevant pathways included MAPK signaling pathway (Q=0.16), and Neurotrophin signaling pathway, (Q=0.41)

Conclusion: The findings of this pilot study suggest that miR-3151-5p, miR-1307-5p, miR-656-3p, and miR-520c-3p mediate neuropathic pain in patients with RA. In addition, they point to Neurotrophin and MAPK signaling pathways as important targets of miRNA deregulation of neuropathic pain in these patients, thus making them potential mechanisms to consider in developing treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identifying-micrornas-associated-with-neuropathic-pain-in-patients-with-rheumatoid-arthritis-ra/