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Cited by 166Rheumatoid Arthritis Research and TherapiesMicroRNA in disease regulationNatural Compounds in Disease Treatment

Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα

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Castro-Villegas, Carmen, Pérez-Sánchez, Carlos, Escudero, Alejandro, Filipescu, Ileana, Verdu, Miriam, Ruiz-Limón, Patricia, Aguirre, Ma Angeles, Jiménez-Gomez, Yolanda +8 more·2015·Arthritis Research & Therapy
DOI 10.1186/s13075-015-0555-zPMC PMC4377058
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Abstract

Introduction: The advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNFα therapy in RA patients. Methods: In total, 95 RA patients undergoing anti-TNFα/disease-modifying antirheumatic drugs (anti-TNFα/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6 months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNFα/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed. Results: Ninety percent of RA patients responded to anti-TNFα/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation - especially on chondrocytes - as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNFα/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. Further, we identified a specific plasma miRNA signature (miR-23 and miR-223) that may serve both as predictor and biomarker of response to anti-TNFα/DMARDs combination therapy. Conclusions: miRNA levels in the serum of RA patients before and after anti-TNFα/DMARDs combination therapy are potential novel biomarkers for predicting and monitoring therapy outcome.

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  • Abnormal expression levels of miR-23 enable it to serve as a potential biomarker for diagnosis and progression of metabolic and immune disorders.

    “To date, some studies have shown that abnormal expression levels of miR-23 enable it to serve as a potential biomarker for the diagnosis and progression of diseases such as metabolic and immune disorders [12,13].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [13]

    The Results section ('Serum miRNAs hsa-miR-23a-3p and hsa-miR-223-3p as predictors of therapy response in RA patients'; page unavailable) suggests miR-23a-3p can help predict and monitor treatment response in rheumatoid arthritis, an immune disorder. It does not establish miR-23 as a biomarker for diagnosing disease or tracking its progression, and it provides no corresponding finding for metabolic disorders. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Overexpression of CXCL12 activates the NF-κB signaling pathway to promote inflammation.

    “Overexpression of CXCL12 activates the NF-κB signaling pathway to promote inflammation [13,31].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [13]

    The Discussion (page unavailable) links NF-κB to proinflammatory factors in rheumatoid arthritis and says CHUK mediates NF-κB activation. It does not say that CXCL12 overexpression activates this pathway; searches for CXCL12 and its alternative name SDF-1 found no supporting passage. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • Expression levels of miR-23a were de-regulated in RA patient samples compared to healthy synovial tissue and serum samples, while miR-23-3p in serum was significantly upregulated by anti-TNFα/DMARDs combination therapy.

    “Clinical researches have revealed that the expression levels of miR-23a were de-regulated in RA patient samples compared to healthy synovial tissue and serum samples, while miR-23–3p in serum was significantly upregulated by anti-TNFα/DMARDs combination therapy.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [13]

    The Results section, “Validation of the differentially expressed miRNAs” (page unavailable), reports that serum miR-23-3p increased significantly after anti-TNFα/DMARD combination therapy in the RA patients studied. The cited paper does not establish the claimed comparison of miR-23a expression in RA samples with healthy synovial tissue and serum samples; its reported comparison is before versus after treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • miR-23 targets CXCL12 to modulate the NF-κB signaling pathway, leading to decreased TNF-α, IL-1β, and IL-8 expression levels, which inhibit inflammation and enhance RA.

    “Further investigation has demonstrated that miR-23 targets C-X-C motif ligand 12 (CXCL12) to modulate the NF-κB signaling pathway, leading to decreased TNF-α, IL-1β, and IL-8 expression levels which inhibit inflammation and enhance RA.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [13]

    The Results (Regulation network; page unavailable) list CHUK as a potential target of miR-23, and the Discussion (page unavailable) explains that CHUK mediates NF-κB activation. The paper does not identify CXCL12 as a miR-23 target or show that miR-23 lowers TNF-α, IL-1β, and IL-8 through that pathway; its proposed targets are not evidence of the claimed causal sequence. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 37

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Authors
Castro-Villegas, C., Pérez-Sánchez, C., Escudero, A., Filipescu, I., Verdu, M., Ruiz-Limón, P., Aguirre, M. A., Jiménez-Gomez, Y., Font, P., Rodriguez-Ariza, A., Peinado, J. R., Collantes-Estévez, E., González-Conejero, R., Martinez, C., Barbarroja, N., & López-Pedrera, C.
Affiliations
  • Iuliu Hațieganu University of Medicine and Pharmacy (RO)
  • Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
  • University of Castilla-La Mancha (ES)
Corresponding author
López-Pedrera, Chary
ORCID
Venue
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2015-03-09
Volume
17
Issue
1
Pages
49-49
ISSN
1478-6354 (ISSN-L)
DOI
10.1186/s13075-015-0555-z
PMC
PMC4377058
OpenAlex
W4253796858
Cited by
166
References
37
Citations by year
2026: 3 · 2025: 8 · 2024: 9 · 2023: 15 · 2022: 13 · 2021: 17 · 2020: 23 · 2019: 14 · 2018: 23 · 2017: 18 · 2016: 17 · 2015: 6
FWCI
17.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Arthritis Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Universidad de Córdoba Insitutional Repository (Universidad de Córdoba) (submittedVersion, cc-by-nc-nd)
Funders
  • Junta de Andalucía (CTS-7940)
  • Fundación Española de Reumatología
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
rheumatoid arthritis, circulating microRNAs, anti-TNF therapy, predictive biomarkers, treatment response, serum microRNA expression, miR-146a, miR-223-3p, miR-125b-5p, miR-126-3p, miR-16-5p, TNF-α, interleukin-6, IL-17
MeSH terms
Adult, Aged, Arthritis, Rheumatoid, Female, Humans, Male, Middle Aged, Tumor Necrosis Factor-alpha, Biomarkers, Antirheumatic Agents, MicroRNAs, Young Adult

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