title: Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis.
abstract: OBJECTIVE
  Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab.
  
  
  METHODS
  Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation.
  
  
  RESULTS
  Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317).
  
  
  CONCLUSIONS
  A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Saskia
authors: S
authors: Vosslamber
authors: Hennie G
authors: HG
authors: Raterman
authors: Tineke C T M
authors: TC
authors: van der Pouw Kraan
authors: Marco W J
authors: MW
authors: Schreurs
authors: B Mary E
authors: BM
authors: von Blomberg
authors: Michael T
authors: MT
authors: Nurmohamed
authors: Willem F
authors: WF
authors: Lems
authors: Ben A C
authors: BA
authors: Dijkmans
authors: Alexandre E
authors: AE
authors: Voskuyl
authors: Cornelis L
authors: CL
authors: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D015415:Biomarkers; D007370:Interferon Type I; D000069283:Rituximab