Circulating MicroRNAs as Potential Biomarkers for Monitoring the Response to In Vivo Treatment with Rituximab in Systemic Lupus Erythematosus

Carlos Perez-Sanchez¹, Irene Cecchi ², Laura Pérez-Sanchez ³, Alejandra Patiño-Trives ⁴, Nuria Barbarroja ⁵, Maria Luque-Tevar ⁴, Alejandro Ibañez-Costa ⁴, Ivan Arias de la Rosa ⁶, Maria del Carmen Abalos-Aguilera ⁴, Rafaela Ortega ⁴, Alejandro Escudero ⁷, Massimo Radin ², Savino Sciascia ⁸, Mª Ángeles Aguirre-Zamorano ⁷, Eduardo Collantes-Estevez ⁶ and Chary Lopez-Pedrera ⁴, ¹Rheumatology service, IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, Cordoba, Spain, ²University of Turin, Turin, Italy, ³MIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, ⁴IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, ⁵University of Cordoba/IMIBIC/Reina Sofia Hospital and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Cordoba, Spain, ⁶University of Cordoba/IMIBIC/Reina Sofia Hospital, Cordoba, Spain, ⁷IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, ⁸Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, Torino, Italy

Meeting: ACR/ARP Annual Meeting 2019

Keywords: Rituximab, systemic lupus erythematosus (SLE) and biomarkers

Session Information

Date: Monday, November 11, 2019

Title: SLE – Etiology & Pathogenesis Poster I

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Recent studies have highlighted the potential role of microRNAs (miRNAs) as diagnostic and prognostic biomarkers in Systemic Lupus Erythematosus (SLE). While Rituximab (RTX) represents an important therapeutic option, identifying those patients who might benefit from this approach is still an unmet clinical need. This study aimed to analyze the circulating miRNAs profile in SLE patients’ serum and the modulatory effect of RTX.

Methods: Twenty-seven healthy donors (HDs) and 25 SLE patients were recruited. SLE patients were clinically and serologically evaluated at baseline and after 3-month RTX treatment (375 mg/sq weekly / 4 weeks). Clinical assessment included changes in disease activity, using the SLE Disease Activity Index 2000 (SLEDAI-2K) and complete serological evaluation. Whole miRNome profile of serum samples was performed in an exploratory cohort of HDs and SLE patients before and after RTX therapy. The functional classification and target gene prediction of altered miRNAs was interrogated by Ingenuity Pathway Analysis software (IPA), which allowed us to select a set of miRNAs whose expression was validated by qPCR in the whole cohorts of patients and HDs. Changes in the levels of potential inflammatory mediators modulated by these miRNAs was also evaluated by multiplex assay.

Results: After 3-month RTX therapy, active SLE patients (SLEDAI-2K=9,5) showed a significant reduction in disease activity (SLEDAI-2K=1,5) along with reduced acute phase reactants (CRP and ESR) levels, and anti-dsDNA titers. miRNome profile showed altered expression of 153 miRNAs in SLE at baseline when compared to HDs (cut-off: 2-fold change): 142 increased and 11 reduced. Among those, the expression of 121 out of 153 (79%) miRNAs were reverted by in vivo treatment with RTX. The functional classification of these miRNAs revealed their association with clinical features of the SLE physiopathology such as inflammatory response, renal and haematological disease, connective tissue disorders and neurological, cardiovascular and dermatological disease, among others.

By using IPA analysis, we identified a panel of 5 microRNAs (miR-149-3p, 125b-5p, 199a-5p, 106b-3p 124-3p) that showed potential targets molecules comprising key pro-inflammatory cytokines and immune receptors, along with a high number of molecules that control intracellular pathways associated with inflammatory and autoimmune processes. The altered expression of these selected miRNAs in SLE patients’ serum vs HD was further validated in the entire cohort, along with the effect of RTX in the reversion of those levels.

Accordingly, the reestablishment of the altered circulating miRNA profile of SLE patients was accompanied by the downregulation of a set of pro-inflammatory cytokines found elevated in SLE serum, including IFNg, TNFa, IL6 and IL8.

Conclusion: Our overall data support the role of specific miRNAs as biomarkers for monitoring the response to B-depletion treatment in SLE, allowing an early identification of those patients who could benefit more from this therapy, and ultimately leading to a more tailored approach.

Funded by ISCIII, PI18/00837 and RIER RD16/0012/0015 co-funded with FEDER

Figure 1 Autoimmunity Review-v1

Disclosure: C. Perez-Sanchez, None; I. Cecchi, None; L. Pérez-Sanchez, None; A. Patiño-Trives, None; N. Barbarroja, None; M. Luque-Tevar, None; A. Ibañez-Costa, None; I. Arias de la Rosa, None; M. Abalos-Aguilera, None; R. Ortega, None; A. Escudero, None; M. Radin, None; S. Sciascia, None; M. Aguirre-Zamorano, None; E. Collantes-Estevez, None; C. Lopez-Pedrera, None.

To cite this abstract in AMA style:

Perez-Sanchez C, Cecchi I, Pérez-Sanchez L, Patiño-Trives A, Barbarroja N, Luque-Tevar M, Ibañez-Costa A, Arias de la Rosa I, Abalos-Aguilera M, Ortega R, Escudero A, Radin M, Sciascia S, Aguirre-Zamorano M, Collantes-Estevez E, Lopez-Pedrera C. Circulating MicroRNAs as Potential Biomarkers for Monitoring the Response to In Vivo Treatment with Rituximab in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/circulating-micrornas-as-potential-biomarkers-for-monitoring-the-response-to-in-vivo-treatment-with-rituximab-in-systemic-lupus-erythematosus/. Accessed .

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