title: Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis.
abstract: The aim of this study was to investigate the influence of clinical and genetic factors on response to tocilizumab (TCZ) response, remission, low disease activity (LDA) and DAS28 improvement. A retrospective cohort study in 79 RA patients treated with TCZ during 6/18 months of therapy was conducted. CD69(rs11052877), GALNT18(rs4910008), CLEC2D(rs1560011), KCNMB1(rs703505), ENOX1(rs9594987), rs10108210, and rs703297 gene polymorphisms, identified in a recent GWAS as putative predictors of TCZ response, were analysed. Variables independently associated to satisfactory EULAR response at 6 months were GALNT18-CC genotype (ORCC/T-:12.8; CI95%:1.5,108.7; p=0.02), CD69 gene polymorphism (ORAA/GG:17.2; CI95%:2.5,119.6; p=0.004) and lower number of previous biological therapy, BT (OR: 0.45; CI95%:0.3, 0.7; p=0.001). The factors independently associated to higher remission were lower number of previous BT (OR:0.56; CI95%:0.38, 0.82; p=0.003), and GALNT18 CC genotype (ORCT/CC:0.09; CI95%:0.02,0.45;p=0.004; ORTT/CC:0.14; CI95%:0.02,0.79; p=0.026). The A-allele of CD69 (ORA_/GG:6.68;CI95%:1.68,26.51;p=0.007) and lower number of previous BT (OR:0.50; CI95%:0.32,0.77; p=0.002) were independent factors capable to predict higher LDA rates at 6 months. Independent factors associated to higher improvement in DAS28 at 6 months were CD69-AA genotype (B=-0.56; CI95%:-1.09, -0.03; p=0.039), GALNT18-CC genotype (B=-0.88;CI95%:-1.49, -0.27; p=0.005), subcutaneous administration (B=1.03; CI95%:0.44,1.62; p=0.001) and higher baseline DAS28 (B=0.82; CI95%:0.59, 1.05; p=4.9×10(-10)). Lower number of previous BT was the only independent predictor of satisfactory EULAR response (OR:0.60; CI95%:0.34,0.88; p=0.010) and higher remission (OR:0.65; CI95%:0.46,0.93; p=0.018) at 18 months. The C-allele of GALNT18 (ORC-/TT:4.60; CI95%:1.16, 18.27; p=0.03) and lower number of previous BT (OR:0.47; CI95%:0.29,0.74; p=0.001) were independent factors capable to predict higher LDA rates at 18 months. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates in patients carrying the GALNT18 C-allele or the CD69 A-allele, particularly when lower number of BT were previously administered.
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: mariadelmarmaldonadomontoro@gmail.com.
authors.forename: Mar
authors.initials: M
authors.lastname: Maldonado-Montoro
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: marisacgarre@gmail.com.
authors.forename: Marisa
authors.initials: M
authors.lastname: Cañadas-Garre
authors.affiliation: UGC Rheumatology, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain,. Electronic address: agutrilla@wanadoo.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: González-Utrilla
authors.affiliation: Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Av. Vicuña Mackenna 4860, Santiago.7820436, Chile. Electronic address: jplaza@uc.cl.
authors.forename: José Cristian
authors.initials: JC
authors.lastname: Plaza-Plaza
authors.affiliation: Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain. Electronic address: mangel.calleja.sspa@juntadeandalucia.es.
authors.forename: Miguel Ÿngel
authors.initials: MŸ
authors.lastname: Calleja-Hernández
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D016017:Odds Ratio; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011237:Predictive Value of Tests; D020127:Recovery of Function; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult; D000097763:Polypeptide N-acetylgalactosaminyltransferase; D000099192:CD69 Antigens
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018501:Antirheumatic Agents; D037181:Lectins, C-Type; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; D000099192:CD69 Antigens; C502936:tocilizumab
keywords: CD69; Effectiveness; GALNT18; Rheumatoid arthritis; Tocilizumab