Circulating Biomolecules as Potential Biomarkers of Early and Establishedresponse to TNFi Therapy in Rheumatoid Arthritis Patients

Chary Lopez-Pedrera¹, Maria Luque-Tevar¹, Carlos Pérez-Sánchez¹, Pilar Font², Alejandra Maria Patiño-Trives¹, Iván Arias de la Rosa¹, María-Carmen Abalos-Aguilera¹, Carmen Torres-Granados¹, Montserrat Romero-Gomez², Desirée Ruiz-Vilchez², Rafaela Ortega-Castro³, Alejandro Escudero-Contreras⁴, Carlos Rodriguez-Escalera⁵, Jose Perez-Venegas⁶, Mª Dolores Ruiz-Montesinos⁶, Carmen Dominguez⁶, Carmen Romero-Barco⁷, Antonio Fernandez-Nebro⁸, Natalia Mena-Vazquez⁹, Jose Luis Marenco¹⁰, Julia Uceda-Montañez¹⁰, Mª Dolores Toledo-Coello¹¹, Nuria Barbarroja⁴, M Angeles Aguirre² and Eduardo Collantes², ¹Rheumatology Department, Reina Sofia University Hospital/ Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ University of Cordoba, Cordoba, Spain, Cordoba, Spain, ²Rheumatology Department, Reina Sofia University Hospital/ Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ University of Cordoba, Cordoba, Spain, Córdoba, Spain, ³Hospital Universitario Reina Sofía, Córdoba, Spain, ⁴IMIBIC/Hospital Reina Sofia /Universidad de Cordoba., Córdoba, Spain, ⁵Hospital Universitario de Jaen, Jaén, Spain, ⁶Hospital Universitario Virgen Macarena, Sevilla, Sevilla, Spain, ⁷Hospital Clínico Universitario, Málaga, Málaga, Spain, ⁸University of Malaga, Malaga, Spain, ⁹Hospital Regional Universitario de Málaga, Málaga, Spain, ¹⁰Hospital Universitario Virgen de Valme, Sevilla, Sevilla, Spain, ¹¹Hospital Universitario de Jerez de la Frontera, Cádiz, Spain, Cádiz, Spain

Meeting: ACR Convergence 2020

Keywords: Anti-TNF Drugs, Biomarkers, Micro-RNA, rheumatoid arthritis

Session Information

Date: Monday, November 9, 2020

Title: RA – Treatments III: Predictors of Treatment Response (2003–2007)

Session Type: Abstract Session

Session Time: 4:00PM-4:50PM

Background/Purpose: To evaluate changes produced in circulating inflammatory mediators and their regulatory miRNAs in RA patients after 3 and 6 months of treatment with TNF-α inhibitors (TNFi), in order to identify biomarkers of clinical efficacy and potential predictors of therapeutic response to TNFi therapies.

Methods: In a prospective RA cohort multicenter study, serum from125 RA patients with moderate/high disease activity was collected prior and after 3 and 6 months of TNFi treatment. Patients’ response was determined according to EULAR response criteria. The inflammatory profile was analyzed by using a multiplex immunoassay and circulating levels of several microRNAs -whose potential targets were mRNAs encoding inflammatory proteins- were evaluated. Then, their discriminative ability was evaluated. To assess the added value of these biomolecules, logistic prediction models were created.

Results: Among RA patients, 79% (99/125) showed early response after 3 months of TNFi treatment, of which a 67% (66/99) showed clinical response after 6 months of therapy. Inflammatory mediators related to activation and proliferation (IL-6, IL-13), adhesion and migration (MIP-1a, RANTES, FGFb), chemotaxis (MIP1-b, IL8, IP-10) and angiogenesis (VEGF), showed a trend to reduction after 3 months, but were significantly downregulated only after 6 months of TNFi therapy. In addition, several molecules upregulated after 3 months of TNFi therapy -involved in cell activation and differentiation (IFNg, GM-CSF, IL-4, IL-5), immunoregulation (IL-1RA, IL-10) and migration (MCP-1, PDGFb)- were thereafter downregulated, consolidating the reduction in the inflammatory response. Moreover, a decline in 7 of these molecules correlated with DAS28 reduction.

In the search for predictors of response to this drug, clinical and molecular parameters were evaluated. High DAS28/SDAI scores or levels of auto-antibodies (RF or ACPA) at baseline were not predictive of response to the treatment. Instead, atherogenic index, smoking habit and hyperlipidemia at baseline were predictors of a worse response to TNFi therapy. Moreover, both, baseline microRNAs and inflammatory profiles clearly distinguished among patients with differential therapeutic response. High baseline levels of inflammatory mediators related to the leukocyte activation and proliferation, adhesion and migration, along with high baseline levels of several microRNAs (miR-106a-5p, miR-199a-5p, miR-346, miR-223-3p, and miR-143-5p) regulating their expression, were predictive of response to TNFi treatment both, at 3 and 6 months.

Receiver operating characteristic (ROC) analyses for those biomarkers allowed us to further identify specific signatures of circulating biomolecules that may serve as predictors of response to TNFi therapy with high sensitivity and specificity.

Conclusion: The extensive analysis of the serum inflammatory and microRNAs profiles allowed identifying specific and distinctive signatures of biomolecules that, in coordination with known clinical and serological profiles, might predict early and established response of RA patients to TNFi treatment.
Funded by PI-0285-2017, ISCIII (PI18/00837) and RIER RD16/0012/0015, co-funded with FEDER

Disclosure: C. Lopez-Pedrera, None; M. Luque-Tevar, None; C. Pérez-Sánchez, None; P. Font, None; A. Patiño-Trives, None; I. Arias de la Rosa, None; M. Abalos-Aguilera, None; C. Torres-Granados, None; M. Romero-Gomez, None; D. Ruiz-Vilchez, None; R. Ortega-Castro, None; A. Escudero-Contreras, None; C. Rodriguez-Escalera, None; J. Perez-Venegas, None; M. Ruiz-Montesinos, None; C. Dominguez, None; C. Romero-Barco, None; A. Fernandez-Nebro, Roche, 1, Nordic, 1, Stada, 1, Sanofi, 1, Janssen, 1, Pfizer, 1, Abbvie, 1, Novartis, 1, Gedeon, 1, Lilly, 1; N. Mena-Vazquez, None; J. Marenco, None; J. Uceda-Montañez, None; M. Toledo-Coello, None; N. Barbarroja, None; M. Aguirre, None; E. Collantes, Abbvie Inc, 5, 8, Amgen, 5, 8, Eli Lilly and Company, 5, 8, Janssen Pharmaceutical, 5, 8, MSD, 5, 8, Novartis, 5, 8, Pfizer Inc, 5, 8, UCB, 5, 8.

To cite this abstract in AMA style:

Lopez-Pedrera C, Luque-Tevar M, Pérez-Sánchez C, Font P, Patiño-Trives A, Arias de la Rosa I, Abalos-Aguilera M, Torres-Granados C, Romero-Gomez M, Ruiz-Vilchez D, Ortega-Castro R, Escudero-Contreras A, Rodriguez-Escalera C, Perez-Venegas J, Ruiz-Montesinos M, Dominguez C, Romero-Barco C, Fernandez-Nebro A, Mena-Vazquez N, Marenco J, Uceda-Montañez J, Toledo-Coello M, Barbarroja N, Aguirre M, Collantes E. Circulating Biomolecules as Potential Biomarkers of Early and Establishedresponse to TNFi Therapy in Rheumatoid Arthritis Patients [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/circulating-biomolecules-as-potential-biomarkers-of-early-and-establishedresponse-to-tnfi-therapy-in-rheumatoid-arthritis-patients/. Accessed .

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