LAUSR

Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease with unknown etiology [1]. Characteristic features of RA are chronic synovitis and a fluctuating clinical course, eventually leading to joint deformities or even long-term disability [1], and thereby carrying a substantial burden for both the individual and society [2]. Early diagnosis is the key for successful treatment, particularly in patients with risk factors for poor prognostic (including high disease activity, presence of autoantibodies, and early joint damage) [3]. Although standard diagnostic criteria are now available for existed RA diagnosis, the most important challenging issue remains to find biomarkers for early diagnosis, especially for patients who cannot be made a specific diagnosis at first presentation, and their exclusive diagnosis is undifferentiated arthritis [4]. Accumulating evidences show that microRNAs (miRNAs) can be aberrantly expressed in both inflamed synovium and circulation of RA patients [5], and the role of miRNAs in RA might fulfill the criteria for their using as novel molecular diagnostic markers for RA [6]. Here, we read with great interest the articles and provide an expert review of miRNAs in diagnostics in patients with RA. miRNAs are endogenous, single-stranded, non-coding RNAs that are evolutionarily conserved with a length of 18–25 nucleotides [7]. miRNAs can influence the target mRNA processing at the post-transcriptional level by promoting mRNA degradation or translational repression [8]. The first evidence for miRNAs’ role in human diseases was shown in cancer cells, which opened up the exciting prospect of using miRNAs as powerful, non-invasive biomarkers for immune responses and autoimmune diseases [9]. In 2007, Bhanji and colleagues first discovered that miRNAs might play a role in RA progression [10]. Over the following year, subsequent studies reported the dysregulation of certain miRNAs within inflamed joints and in the peripheral circulation of patients with RA, and these specific miRNAs were miR-16, miR-132, miR-146a, and miR-155 [11–13]. Since then, much has been learned about the majority of miRNAs involved in the natural course of RA, and those studies to date have mainly focused on synovial tissue/fluid and peripheral blood from established RA, often in minimally defined and heterogeneous cohorts. The dysregulation of miRNAs in inflamed joints from RA has been demonstrated by a number of works in literature. There is a study showing that the expression levels of miR-16, miR146a, miR-155 and miR-223 were significantly increased in synovial fluid of RA patients, which may differentiate RA from osteoarthritis (OA). Several other studies showed that in RA synovial fibroblasts (RASFs) isolated from inflamed joints of RA patients, miR-133a, miR-142-3p, miR-142-5p, miR-146a, miR-155, miR-203, miR-221/miR-222 cluster, miR-223 and miR-323-3p presented with the increased expression, while the expression of miR-124a and miR-34a* were decreased [13–18]. Mechanism study showed that both miR-124a and miR-34a* can inhibit synovial cell proliferation [15,16]. In synovial tissue, miR-146a, miR-146b, miR-150, miR-155, miR-223 were obviously high-expressed, while miR-22, miR-23b, and miR-30a were downregulated [12,13,19–23]. Moreover, in synovial fluid CD4+cell in RA joints, the reports showed that the miR-21, miR-363 and miR-498 were significantly lowexpressed, while the expression level of miR-146a was changed in an opposite trend [24]. In addition, there was an upregulated expression of miR-146 and miR-155 in both synovial fluid CD4+cell and synovium macrophages [11–13,25]. It is believed that synovial tissues, RASFs, and peripheral blood mononuclear cell (PBMC) secret miRNAs in distinct patterns [14]. In PBMC, seven miRNAs (miR-16, miR-26a, miR-132, miR-146a, miR-146b, miR-150, and miR-155) were reported to be significantly increased, and interestingly only miR-21 was found to be significantly decreased [11,22,26]. The abnormal expression of miRNAs in the blood of patients with RA was also discovered and addressed in many studies. There are amount data showing that the expression levels of nine miRNAs (miR-16, miR-21, miR-24, miR-26a, miR125a-5p, miR-125b, miR-126-3p, miR-223 and miR-451) were increased in serum/plasma from RA patients whereas six miRNAs (miR-16, miR-125a-3p, miR-126-3p, miR-132, miR146a and miR-155) were significantly downregulated [14,27– 30]. Of note, the miR-16 and miR-126-3p can be upregulated and also downregulated in RA serum/plasma, which is controversial and need to be re-studied. In the whole blood, many miRNAs were found to be significantly overexpressed, and they are miR-99, miR-100, miR-125b, miR-146a and miR-155