title: Identification of S100A9 as biomarker of responsiveness to the methotrexate/etanercept combination in rheumatoid arthritis using a proteomic approach.
abstract: OBJECTIVE
  One way to optimize the drug prescription in rheumatoid arthritis (RA) is to identify predictive biomarkers of drug responsiveness. Here, we investigated the potential "theranostic" value of proteins of the S100 family by monitoring levels of both S100A8 and S100A9 in blood samples from RA patients.
  
  
  METHODS
  For proteomic analysis, peripheral blood mononuclear cells (PBMC) and serum samples were collected in patients prior to initiation of the methotrexate/etanercept (MTX/ETA) combination. Firstly, relative mass spectrometry (MS) quantification focusing on S100A8 and S100A9 proteins was carried out from PBMCs samples to identify potential biomarkers. The same approach was also performed from serum samples from responder (R) and non responder (NR) patients. Finally, to confirm these results, an absolute quantification of S100A8, S100A9 proteins and calprotectin (heterodimer of S100A8/S100A9) was carried out on the serum samples using ELISA.
  
  
  RESULTS
  MS analyses revealed that both S100A8 and S100A9 proteins were significantly accumulated in PBMC from responders. In contrast to PBMC, only the S100A9 protein was significantly overexpressed in the serum of R patients. Absolute quantification by ELISA confirmed this result and pointed out a similar expression level of S100A8 protein and calprotectin in sera from both R and NR groups. Thus, the S100A9 protein revealed to be predictive of MTX/ETA responsiveness, contrarily to parameters of inflammation and auto-antibodies which did not allow significant discrimination.
  
  
  CONCLUSIONS
  This is the first report of an overexpression of S100A9 protein in both PBMCs and serum of patients with subsequent response to the MTX/ETA combination. This protein thus represents an interesting biomarker candidate of therapeutic response in RA.
authors.affiliation: INSERM, U905, Pathophysiology and Biotherapy of Inflammatory and Autoimmune Diseases, F-76000 Rouen, France; CNRS, UMR 6270, Polymers, Biopolymers and Surfaces, F-76821 Mont Saint Aignan, France; PISSARO Proteomics Facility, F-76821 Mont Saint Aignan, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Obry
authors.affiliation: INSERM, U905, Pathophysiology and Biotherapy of Inflammatory and Autoimmune Diseases, F-76000 Rouen, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France; Department of Rheumatology, Rouen University Hospital, F-76000 Rouen, France; INSERM, Centre d'investigation clinique 1404, F-76000 Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lequerré
authors.affiliation: CNRS, UMR 6270, Polymers, Biopolymers and Surfaces, F-76821 Mont Saint Aignan, France; PISSARO Proteomics Facility, F-76821 Mont Saint Aignan, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Hardouin
authors.affiliation: INSERM, U905, Pathophysiology and Biotherapy of Inflammatory and Autoimmune Diseases, F-76000 Rouen, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France; Department of Immunology, Rouen University Hospital, F-76000 Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: Department of Rheumatology, Amiens University Hospital, F-80000 Amiens Cedex 1, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Fardellone
authors.affiliation: of Rheumatology, University Hospital of Lille, F-59037 Lille Cedex, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Philippe
authors.affiliation: INSERM, U905, Pathophysiology and Biotherapy of Inflammatory and Autoimmune Diseases, F-76000 Rouen, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France; Department of Rheumatology, Rouen University Hospital, F-76000 Rouen, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Le Loët
authors.affiliation: CNRS, UMR 6270, Polymers, Biopolymers and Surfaces, F-76821 Mont Saint Aignan, France; PISSARO Proteomics Facility, F-76821 Mont Saint Aignan, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Cosette
authors.affiliation: INSERM, U905, Pathophysiology and Biotherapy of Inflammatory and Autoimmune Diseases, F-76000 Rouen, France; Normandy University, Institute of Research and Innovation in Biomedecine, F-76821 Mont Saint Aignan, France; Department of Rheumatology, Rouen University Hospital, F-76000 Rouen, France; INSERM, Centre d'investigation clinique 1404, F-76000 Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Vittecoq
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism*; D054316:Biomarkers, Pharmacological / Q000737:chemistry / Q000378:metabolism*; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000737:chemistry / Q000378:metabolism*; D015331:Cohort Studies; D004338:Drug Combinations; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D054316:Biomarkers, Pharmacological; D040501:Calgranulin A; D040502:Calgranulin B; D004338:Drug Combinations; D007074:Immunoglobulin G; D039841:Leukocyte L1 Antigen Complex; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept; D008727:Methotrexate