title: Variations in the metabolome in response to disease activity of rheumatoid arthritis.
abstract: Anti-Tumor Necrosis Factor (TNF) therapies are able to control rheumatoid arthritis (RA) disease activity and limit structural damage. Yet no predictive factor of response to anti-TNF has been identified. Metabolomic profile is known to vary in response to different inflammatory rheumatisms so determining it could substantially improve diagnosis and, consequently, prognosis. The aim of this study was to use mass spectrometry to determine whether there is variation in the metabolome in patients treated with anti-TNF and whether any particular metabolomic profile can serve as a predictor of therapeutic response.
  
  
  
  Blood samples were analyzed in 140 patients with active RA before initiation of anti-TNF treatment and after 6 months of Anti-TNF treatment (100 good responders and 40 non-responders). Plasma was deproteinized, extracted and analyzed by reverse-phase chromatography-QToF mass spectrometry. Extracted and normalized ions were tested by univariate and ANOVA analysis followed by partial least-squares regression-discriminant analysis (PLS-DA). Orthogonal Signal Correction (OSC) was also used to filter data from unwanted non-related effects. Disease activity scores (DAS 28) obtained at 6 months were correlated with metabolome variation findings to identify a metabolite that is predictive of therapeutic response to anti-TNF.
  
  
  
  After 6 months of anti-TNF therapy, 100 patients rated as good responders and 40 patients as non-responders according to EULAR criteria. Metabolomic investigations suggested two different metabolic fingerprints splitting the good-responders group and the non-responders group, without differences in anti-TNF therapies. Univariate analysis revealed 24 significant ions in positive mode (p < 0.05) and 31 significant ions in negative mode (p < 0.05). Once intersected with PLS results, only 35 ions remained. Carbohydrate derivates emerged as strong candidate determinants of therapeutic response.
  
  
  
  This is the first study describing metabolic profiling in response to anti-TNF treatments using plasma samples. The study highlighted two different metabolic profiles splitting good responders from non-responders.
authors.affiliation: Rheumatology Department, CHU Gabriel Montpied, 58 rue Montalembert B.P. 392, 63011, Clermont-Ferrand, France. ztatar@chu-clermontferrand.fr.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tatar
authors.affiliation: Metabolomics Platform, INRA, Clermont-Ferrand, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Migne
authors.affiliation: Metabolomics Platform, INRA, Clermont-Ferrand, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Petera
authors.affiliation: Rheumatology Department, CHU Grenoble-Hôpital Sud, Echirolles, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaudin
authors.affiliation: CHU Bois-Guillaume, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lequerre
authors.affiliation: INSERM 1059, Université de Lyon, Saint-Etienne, France.|Rheumatology Department, CHU Saint-Etienne, Saint-Etienne, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Marotte
authors.affiliation: Rheumatology Department, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Tebib
authors.affiliation: Metabolomics Platform, INRA, Clermont-Ferrand, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Pujos Guillot
authors.affiliation: Rheumatology Department, CHU Gabriel Montpied, 58 rue Montalembert B.P. 392, 63011, Clermont-Ferrand, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Soubrier
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D056148:Chromatography, Reverse-Phase; D016002:Discriminant Analysis; D000068800:Etanercept / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055442:Metabolome; D008875:Middle Aged; D011379:Prognosis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept
keywords: Anti-TNF-alpha therapy; Drug response biomarkers; Metabolomics; Rheumatoid arthritis