title: The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.
abstract: BACKGROUND
  B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.
  
  
  METHODS
  In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).
  
  
  RESULTS
  Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria.
  
  
  CONCLUSIONS
  This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.
authors.affiliation: Department of Rheumatology, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands. c.verweij@vumc.nl.
authors.forename: Hennie G
authors.initials: HG
authors.lastname: Raterman
authors.forename: Saskia
authors.initials: S
authors.lastname: Vosslamber
authors.forename: Sander
authors.initials: S
authors.lastname: de Ridder
authors.forename: Michael T
authors.initials: MT
authors.lastname: Nurmohamed
authors.forename: Willem F
authors.initials: WF
authors.lastname: Lems
authors.forename: Maarten
authors.initials: M
authors.lastname: Boers
authors.forename: Mark
authors.initials: M
authors.lastname: van de Wiel
authors.forename: Ben A C
authors.initials: BA
authors.lastname: Dijkmans
authors.forename: Cornelis L
authors.initials: CL
authors.lastname: Verweij
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
mesh_terms: D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007370:Interferon Type I / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D000069283:Rituximab; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D007370:Interferon Type I; D000069283:Rituximab