Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis

• DOI: 10.3389/fimmu.2021.631662
• Publication Date: 2021-03-23T08:55:47Z
• Authors: Maria Luque-Tévar; Carlos Perez-Sanchez; Alejandra Mª Pati...; Nuria Barbarroja; Ivan Arias de la ...; Mª Carmen Abalos-...; Juan Antonio Mari...; Desiree Ruiz-Vilchez; Rafaela Ortega-Ca...; Pilar Font; Clementina Lopez-...; Montserrat Romero...; Carlos Rodriguez-...; Jose Perez-Venegas; Mª Dolores Ruiz-M...; Carmen Dominguez; Carmen Romero-Barco; Antonio Fernandez...; Natalia Mena-Vazquez; Jose Luis Marenco; Julia Uceda-Montañez; Mª Dolores Toledo...; M. Angeles Aguirre; Alejandro Escuder...; Eduardo Collantes...; Chary Lopez-Pedrera
• Keywords: rheumatoid arthritis; Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors; Male; Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological; Medical Subject Headings::Phenomena and Processes::Mathematical Concepts::Algorithms; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies; Medical Subject Headings::Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, Rheumatoid; Extracellular Traps; Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans; Arthritis, Rheumatoid; Machine Learning; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Sensitivity and Specificity::Predictive Value of Tests; 0302 clinical medicine; Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs; Cluster Analysis; Longitudinal Studies; Prospective Studies; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models; Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents; Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation; Middle Aged; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing; microRNAs; 3. Good health; Medical Subject Headings::Check Tags::Male; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Cluster Analysis; machine learning; Phenotype; Treatment Outcome; Antirheumatic Agents; anti-TNF agents; Female; Medical Subject Headings::Persons::Persons::Age Groups::Adult; Adult; Immunology; NEtosis; 03 medical and health sciences; Medical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Area Under Curve; Predictive Value of Tests; Medical Subject Headings::Persons::Persons::Age Groups::Adult::Middle Aged; Humans; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome; Inflammation; Medical Subject Headings::Check Tags::Female; RC581-607; MicroRNAs; Oxidative Stress; inflammation; Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype; Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies; Tumor Necrosis Factor Inhibitors; Immunologic diseases. Allergy; Biomarkers

Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal in Rheumatoid Arthritis (RA) patients to explore changes serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) built on machine-learning algorithms aimed at the prediction of TNFi response, based profiles RA patients. Methods: A total 104 from two independent cohorts undergoing 29 healthy donors (HD) were enrolled for discovery validation biomarkers. Serum samples obtained baseline 6 months after treatment, therapeutic efficacy was evaluated. inflammatory profile, oxidative stress markers NETosis-derived bioproducts quantified miRNomes recognized by next-generation sequencing. Then, induced delineated. Clinical signatures predictors response assessed with supervised machine learning methods, using regularized logistic regressions. Results: Altered inflammatory, biomolecules found vs. HD, closely interconnected associated specific miRNA profiles. altered profile allowed unsupervised division three clusters patients, showing distinctive phenotypes, further linked effectiveness. Moreover, treatment reversed alterations parallel outcome. Machine-learning cohort identified both, as potential high accuracy, which increased when both features integrated a mixed model (AUC: 0.91). These results confirmed cohort. Conclusions: Our overall data suggest that: 1. anti-TNF-therapy conform profiles, are directly their status baseline. 2. effectiveness divergent among these modulation reestablishment status, reduction NETosis, reversion related miRNAs. 3. The analysis allows identification novel therapy.