Background The advent of 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.
Objectives To investigate serum miRNA levels during the induction therapy by anti-TNFα drugs in RA patients in order to identify possible biomarkers, which could be predictive of the therapeutic effect of anti-TNFα.
Methods Ninety five RA patients undergoing anti-TNFα therapy (54 treated with infliximab, 25 with etanercept and 15 with adalimumab) were enrolled. Serum samples for miRNA analyses were obtained at months 0 and 6, and the therapeutic efficacy of anti-TNFα therapy was assessed. MiRNAs were isolated from the serum of 10 patients before and after anti-TNFα therapy, cDNA transcribed and pooled. With each pool of samples, human serum & plasma miRNA PCR arrays (which identify 84 different miRNAs) were performed. Subsequently, a set of selected miRNAs were analyzed in a validation cohort consisting of miRNA from sera of all the patients included in the study. A number of inflammatory parameters were further analyzed by Flow-cytomix and correlation studies with clinical and serological variables evaluated were also performed.
Results Six-month treatment with anti-TNFα therapy resulted in significant and clinically important improvements in all disease parameters examined (i.e. lower DAS28, SDAI, HAQ, VAS, ESR and CRP). No differences were demonstrated between the therapies administered. Among the serological markers, RF, IL-6 and IL-17 were found reduced. 85.9% of RA patients responded to the induction therapy by anti-TNFα and 18% reached clinical remission. Array analysis identified a 91.1% of miRNAS overexpressed and a 9.9% downregulated after therapy. Functional classification of upregulated miRNAs showed a 60% related to cardiovascular disease, T and B cell activation, inflammation and autoimmunity. Six out of 10 selected miRNAs for validation were found significantly upregulated by anti-TNFα treatment (miR-16, miR-23a, miR125b, miR-126a, miRN-146a, miR-223a). Responder's patients showed a stronger increase in those miRNAs than no responders, in parallel with the reduction of TNFα, IL6, IL17, RF and CRP. Correlation studies demonstrated multiple negative associations between validated miRNAs and clinical (DAS28, SDAI, HAQ, VAS, ESR, CRP), autoimmune (RF) and inflammatory parameters (IL-6).
Conclusions 1. Anti-TNFα therapy in RA patients promote a significant change in the serum levels of a number of miRNAs associated to autoimmunity, inflammation, cardiovascular disease and lymphocyte B and T activation. 2. Close correlations exist among deregulated miRNAs and the positive response to treatment, underlying their potential as biomarkers and novel targets for treatment in patients with RA.
Acknowledgements Supported by: P08-CVI-04234, CTS-7940, PI12/01511, PI11/00566, PI-0191-2013, Spanish Rheumatology Society
Disclosure of Interest None declared
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