Modelo clínico-genético predictivo de no respuesta al tratamiento a largo plazo con los fármacos inhibidores del TNF-α en las Espondiloartritis

• Autores: Jessica Polo Laborda
• Directores de la Tesis: Juan Mulero Mendoza (dir. tes.), María Alejandra Sánchez López (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2017
• Idioma: español
• Número de páginas: 182
• Tribunal Calificador de la Tesis: Juan Antonio Vargas Núñez (presid.), Jose Luis Andreu Sánchez (secret.), Úrsula Muñoz Morón (voc.), M. Leticia Muñoz Zamarrón (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Medicina y Cirugía
• Materias:
  • Ciencias médicas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Spondyloarthritis (SpA) are a group of inflammatory diseases. The ASAS group (Assessment of SpondyloArthritis International Society) classified SpA according to its predominant clinical manifestation (independently of whether or not it is associated with psoriasis, inflammatory bowel disease or a previous history of infection) into: axial SpA (axSpA), characterized by a predominance of sacroiliac joint and/or spine involvement, and peripheral SpA (pSpA) in which peripheral arthritis, enthesitis and/or dactylitis predominate.

    TNF-α inhibitors (TNFi) are effective in controlling SpA activity, however a proportion of patients do not respond to these therapies. New biological therapies, such as IL-17 or IL-12/IL-23 inhibitors, are currently available and are a therapeutic alternative for the management of SpA. Until now, indications for biological therapy are solely based on activity related criteria and resistance to conventional therapy, consequently, prognostic factors are required that will allow the prediction of optimal long-term response to treatment with iTNF-α.

    Several studies have investigated and proposed clinical and genetic factors as response markers, however none of these predictors is sufficiently robust. In addition, the majority have analyzed patients with defined pathological processes and not SpA patients as a whole.

    Therefore we proposed to develop a clinical-genetic predictor of long-term nonresponse to TNFi for use in normal clinical practice in patients diagnosed with SpA according to ASAS criteria. As a result, several clinical variables were analyzed together with 41 single nucleotide polymorphisms (SNPs) associated with response to TNFi in SpA and other inflammatory pathologies. The Cox proportional hazards model was used to analyze the prognostic factors that would affect the non-response rate. The following baseline and genetic factors were shown to have a statistically significant association: global patient assessment (PGA), CRP, BASDAI activity index, BASFI functional index, the number of TNFi used, SNP 916344 of the MAKP14 Resumen/Abstract 4 gene and SNP rs11591741 of the CHUK gene. Of those factors which showed a trend, only female gender demonstrated significance in the multivariate analysis. The variables associated with the non-response rate in the multivariate model were: female gender, which increased the non-response rate by 4.46 times compared to male gender, BASFI, with a 75% increase in the non-response rate for each one point increment, and being a carrier of the GG genotype of the CHUK gene was associated with a non-response rate almost four times higher than patients with CG and CC genotypes.

    Therefore, we propose a clinical-genetic model composed of the above mentioned variables which could be useful to prospectively select patients who would benefit most from treatment with biological therapies