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. 2023 Mar 28:14:980247.
doi: 10.3389/fimmu.2023.980247. eCollection 2023.

Circulating miRNA-19b as a biomarker of disease progression and treatment response to baricitinib in rheumatoid arthritis patients through miRNA profiling of monocytes

Marzena Ciechomska  1 , Leszek Roszkowski  2 , Tomasz Burakowski  1 , Magdalena Massalska  1 , Anna Felis-Giemza  3 , Adria-Jaume Roura  4   5
Affiliations

Circulating miRNA-19b as a biomarker of disease progression and treatment response to baricitinib in rheumatoid arthritis patients through miRNA profiling of monocytes

Marzena Ciechomska et al. Front Immunol. .

Abstract

Introduction: A number of studies have demonstrated a key role of miRNA isolated from cells, tissue or body fluids as disease-specific biomarkers of autoimmune rheumatic diseases including rheumatoid arthritis (RA) and systemic sclerosis (SSc). Also, the expression level of miRNA is changing during disease development, therefore miRNA can be used as biomarkers monitoring RA progression and treatment response. In this study we have investigated the monocytes-specific miRNA that could serve as potential biomarkers of disease progression observed in sera and synovial fluids (SF) in early (eRA) and advanced (aRA) RA and in RA patients before and 3 months after selective JAK inhibitor (JAKi) -baricitinib treatment.

Methods: Samples from healthy control (HC) (n=37), RA (n=44) and SSc (n=10) patients were used. MiRNA-seq of HC, RA, and SSc monocytes was performed to find versatile miRNA present in different rheumatic diseases. Selected miRNAs were validated in body fluids in eRA (<2 years disease onset) and aRA (>2 years disease onset) and RA patients receiving baricitinib.

Results: Using miRNA-seq, we selected top 6 miRNA out of 95 that were significantly changed in both RA and SSc monocytes compared to HC. To identify circulating miRNA predicting RA progression, these 6 miRNA were measured in eRA and aRA sera and SF. Interestingly, miRNA (-19b-3p, -374a-5p, -3614-5p) were significantly increased in eRA sera vs HC and even further upregulated in SF vs aRA sera. In contrast, miRNA-29c-5p was significantly reduced in eRA sera vs HC and even further decreased in SF vs aRA sera. Kegg pathway analysis predicted that miRNA were involved in inflammatory-mediated pathways. ROC analysis demonstrated that miRNA-19b-3p (AUC=0.85, p=0.04) can be used as biomarker predicting JAKi response.

Discussion: In conclusion, we identified and validated miRNA candidates which were present simultaneously in monocytes, sera, SF and that can be used as biomarkers predicting joint inflammation and monitoring therapy response to JAKi in RA patients.

Keywords: JAKi inhibitors; baricitinib; biomarkers; miRNA; monocytes; rheumatoid arthritis; sequencing; synovial fluids.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Global analysis and distribution of miRNA-seq in RA and SSc monocytes. Heatmap of significantly dysregulated miRNA in RA (A) and SSc (B) monocytes compared to HC. Principal component analysis (PCA) plot of global miRNA distribution in RA (green), SSc (blue) and HC (red) monocytes (C). Enrichment analysis of abundantly expressed miRNA regulating selected genes involved in immune pathways in RA (D) and SSc monocytes (E). Heatmap analysis of selected miRNA in RA (F) and SSc (G) monocytes compared to HC.
Figure 2
Figure 2
The level of circulating miRNA in RA and SSc patients. The level of miRNA-19b-3p (A), miRNA-29c-5p (B), miRNA-374a-5p (C), miRNA-503-5p (D), miRNA-589-5p (E), miRNA-3614-5p (F) in sera of RA and SSc patients compared to HC. P-values were expressed as follows: ns for not significant; 0.05 > P > 0.01 as *; 0.01 > P > 0.001 as **; P < 0.001 as ***, P <0.0001 as ****.
Figure 3
Figure 3
The levels of circulating miRNA in body fluids of eRA and aRA patients. The levels of miRNA-19b-3p (A), miRNA-29c-5p (B), miRNA-374a-5p (C), miRNA-503-5p (D), miRNA-589-5p (E), miRNA-3614-5p (F) in sera or eRA and aRA and SF of aRA patients compared to HC. P-values were expressed as follows: ns for not significant; 0.05 > P > 0.01 as *; 0.01 > P > 0.001 as **; P < 0.001 as ***, P <0.0001 as ****.
Figure 4
Figure 4
KEGG pathway analysis of selected 6 miRNA candidates and their potential target genes. The identification of specific pathways (A) and their downstream genes (B) including HLA-DOA and HLA-DQA1, which were predicted to be negatively regulated by significantly changed miRNA in RA patients, using the Diana-miPath tool. The fold change analysis of expression level of HLA class II genes between HC and RA monocytes from RNA-seq (B) based of FDR < 0.01 and p-values < 0.05.
Figure 5
Figure 5
The levels of circulating miRNA in HC and RA patients upon baricitinib therapy. The levels of miRNA-19b-3p (A), miRNA-29c-5p (B), miRNA-374a-5p (C), miRNA-503-5p (D), miRNA-589-5p (E), miRNA-3614-5p (F) before and 3 months after baricitinib treatment in RA patients compared to HC. ROC analysis of changes/delta in miRNA-19b-3p and miRNA-503-5p expression and CRP level upon JAKi therapy (G). Correlation analysis between the expression of delta miRNA-19b-3p and delta DAS28 in baricitinib-treated RA patients (H). P-values were expressed as follows: ns for not significant; 0.05 > P > 0.01 as *; 0.01 > P > 0.001 as **; P < 0.001 as ***, P <0.0001 as ****.
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