**5. Conclusions**

In summary, we have identified two circRNAs and two linear RNAs which are downregulated in patients with positive LS-OCMB status. Our findings are important in the field of biomarkers for multiple sclerosis, given that they could contribute to the identification of patients with highly active disease. Additionally, an important advantage compared to other biomarkers is that they are detected in blood, allowing serial tests to monitor their levels, while this task is not so recommended for lumbar puncture. Future studies in larger cohorts will be needed to confirm their utility, but we consider that they may serve as a first screening tool to decide which patients should go into a lumbar puncture to confirm their LS-OCMB status.

**Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/2227-9059/8/12/540/s1. Table S1: A complete list of samples and the experiment in which each of them were included. Table S2: Assays and primers used in RT-qPCR experiments. Figure S1: Agarose gel electrophoresis image of PCR product and Sanger Sequencing results showing the back-spliced junction of circRNAs.

**Author Contributions:** Conceptualization, D.O. (David Otaegui) and M.M.-C.; methodology, D.O. (David Otaegui), M.M.-C., L.I., T.B., D.O. (Danel Olaverri), and L.M.V.; validation, L.I. and L.S.; formal analysis, L.I., D.O. (Danel Olaverri), T.B., M.M.-C., M.E. and L.C.-F.; investigation, L.I., M.M.-C., M.E., L.C.-F.; resources, A.P., T.C.-T., M.E., L.C.-F., L.M.V. and D.O. (David Otaegui); writing—original draft preparation, L.I., D.O. (David Otaegui) and M.M.-C.; writing—review and editing, D.O. (Danel Olaverri), T.B., Á.P., T.C.-T., L.M.V.; visualization, L.I., D.O. (Danel Olaverri), M.M.-C.; supervision, D.O. (David Otaegui), L.I., M.M.-C. and L.M.V.; project administration, D.O. (David Otaegui) and M.M.-C.; funding acquisition, L.M.V., D.O. (David Otaegui) and M.M.-C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Instituto de Salud Carlos III (PI17/00189 and PI15/00513), Red Española de Esclerosis Múltiple (REEM) (RD16/0015/0007 and RD16/0015/0001), Diputación Foral de Gipuzkoa (109/18) and the Basque Government (PRE\_2019\_2\_0206) and ELKARTEK program.

**Acknowledgments:** Authors want to acknowledge the staff of Genomic Platform at Biodonostia Health Research Institute.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
