Background/Purpose: Despite emerging data on disease-specific associations for various blood- and plasma-derived miRNAs, consensus is lacking as to whether a cellular, extracellular, or a mixed sample might be utilized to define disease mechanisms and serve as biomarkers for therapeutic response. Although studies showed that B-cells are relevant in the development of CVD, the effect of RTX in the context of CVD in SLE patients has not been fully elucidated yet. Objective:To identify and characterize the microRNA profile in SLE monocytes, along with their association with cardiovascular disease (CVD)-related factors, their contribution to the altered miRNA profile in plasma, and their modulation by in vivo RTX treatment.

Methods: Fifty-three SLE patients, and 27 healthy donors were included in the study. Among them, 20 patients were treated with RTX for 3 months. Blood samples were obtained before and at the end of treatment. nCounter microRNA Expression Arrays (NanoString Technologies) and HTG Edgeseq system (Next generation sequencing) were performed, respectively, to analyze miRNA expression profiles on isolated monocytes and plasma. Target genes of the differentially expressed miRNAs were identified by using the Ingenuity Pathway Analysis Software (IPA). A number of altered miRNAs were validated by RT-PCR on the whole cohorts of SLE patients. Extensive clinical/analytical evaluation was performed, and inflammatory, atherosclerosis and pro-thrombotic profiles were quantified by RT-PCR. Then, correlation and association studies were performed.

Results: MicroRNA profiles showed significantly differential expression of 37 microRNAs in SLE monocytes. Functional analysis showed that those miRNAs were mainly related to connective tissue disorders, inflammatory response and reproductive system disease. The expression of several of these miRNAs (i.e. miR-30, miR-149, miR-199) correlated with parameters related to inflammation (i.e. STAT3, PPARg, IL-6, CRP), oxidative stress (mitochondrial membrane potential) and microvascular dysfunction. Moreover, associations of these miRNAs with the occurrence and type of thrombotic events, obstetric complications and presence of early atherosclerosis were demonstrated. Transfection studies further confirmed the relationship between these identified target genes and specific miRNAs. miRNA profile in plasma demonstrated differential expression of 335 microRNAs in SLE patients of which a 60% were reversed by RTX. Among them, 12 miRNAs were found simultaneously deregulated in monocytes and plasma. Interestingly, those 12 miRNAs displayed a number of CVD-related target genes, and were further reversed by in vivo RTX treatment.

Conclusion: We have identified and characterized a specific miRNA profile in monocytes from SLE patients, mostly related to CVD. Although expression from cellular vs circulating miRNAs was mostly divergent in SLE, there was an intriguing association between monocytes and plasma in terms of common deregulated miRNAs involved in CVD, further reversed by RTX treatment.

Funded by CTS7940 and ISCIII (PI15/01333 and RIER RD16/0012/0015)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/contribution-of-monocytes-to-circulating-micrornas-related-to-cardiovascular-disease-in-systemic-lupus-erythematosus-effects-of-in-vivo-treatment-with-rituximab/