A recent study published in Clinical and Experimental Rheumatology has shed new light on the role of circulating microRNAs as predictors of joint damage in patients with early rheumatoid arthritis (RA), offering important implications for treatment strategies involving tumour necrosis factor (TNF) inhibitors such as adalimumab.
MicroRNAs (miRNAs), small non-coding RNA molecules approximately 22 nucleotides in length, have emerged as key regulators of gene expression at the post-transcriptional level. Increasing evidence suggests that they play a central role in RA pathogenesis by modulating inflammatory and immune pathways. These include activation of NF-κB signalling, regulation of apoptosis, and involvement in PI3K/AKT pathways and cytokine production. In particular, miRNAs influence the behaviour of fibroblast-like synoviocytes and peripheral blood mononuclear cells, both of which are central to synovial inflammation and joint damage.
Circulating miRNAs have attracted growing attention as potential minimally invasive biomarkers for diagnosing RA, predicting disease progression, and monitoring therapeutic response. However, their clinical application remains limited due to a lack of large-scale validation studies.
The current findings emerge from a subanalysis of the MIRACLE study, a randomised, open-label, non-inferiority trial involving 134 patients with early RA who had an inadequate response to MTX and were subsequently treated with adalimumab. Researchers measured plasma levels of six specific miRNAs — miR-143-3p, miR-146a-5p, miR-155-5p, miR-182-5p, miR-21-5p, and miR-221-3p — along with serum biomarkers including interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-3 (MMP-3). These were evaluated against structural joint damage assessed using the modified total Sharp score (mTSS), a validated radiographic measure of joint erosion and joint space narrowing.
The analysis revealed that elevated plasma levels of miR-143-3p, miR-146a-5p, miR-21-5p, and miR-221-3p were significantly associated with progression of joint damage over 24 weeks, particularly in terms of joint space narrowing, a key indicator of cartilage loss. In contrast, traditional inflammatory and tissue degradation markers such as IL-6, VEGF, and MMP-3 did not show a significant association with radiographic progression in this cohort.
Cartilage damage was observed more frequently in patients whose MTX dose had been reduced following the initiation of adalimumab. This finding suggests that tapering MTX too early in patients with elevated miRNA levels may increase the risk of structural joint damage, highlighting the need for a more personalised approach to therapy.
These results underscore the potential of circulating miRNAs as predictive biomarkers for cartilage damage in early RA. Beyond their diagnostic value, they may help guide treatment decisions, particularly regarding the optimisation of combination therapy with MTX and biologics. The study also provides further insight into the molecular mechanisms underlying osteocartilage degradation, reinforcing the concept that RA progression is driven not only by systemic inflammation but also by complex gene regulatory networks.
While promising, experts caution that larger, longitudinal studies are needed to validate these findings and determine how best to integrate miRNA profiling into routine clinical practice. If confirmed, such biomarkers could mark a significant step towards precision medicine in rheumatoid arthritis, enabling clinicians to tailor treatment strategies based on an individual patient’s molecular risk profile.
References
- Hosokawa Y, Yoshida Y, Tamai H, Hirata S, Ikeda K, Miyamoto T,et al; MIRACLE study collaborators. Circulating microRNAs associated with tumour necrosis factor or fibloblast-like synoviocyte predict cartilage damage in early rheumatoid arthritis treated with methotrexate plus adalimumab: a subanalysis of the MIRACLE study. Clin Exp Rheumatol. 2026 Mar;44(3):491-498.
- Prajzlerová K, Šenolt L, Filková M. Is there a potential of circulating miRNAs as biomarkers in rheumatic diseases? Genes Dis. 2022 Sep 7;10(4):1263-1278.
- Machaj F, Chmielewska-Jeznach M, Koryszewska-Bagińska A, Malinowski D, Pawlik A, Olędzka G. microRNAs as Biomarkers and Therapeutic Targets in Rheumatoid Arthritis. Int J Mol Sci. 2025 Oct 13;26(20):9950.