title: The gene expression profile in the synovium as a predictor of the clinical response to infliximab treatment in rheumatoid arthritis.
abstract: BACKGROUND
  Although the use of TNF inhibitors has fundamentally changed the way rheumatoid arthritis (RA) is treated, not all patients respond well. It is desirable to facilitate the identification of responding and non-responding patients prior to treatment, not only to avoid unnecessary treatment but also for financial reasons. In this work we have investigated the transcriptional profile of synovial tissue sampled from RA patients before anti-TNF treatment with the aim to identify biomarkers predictive of response.
  
  
  RESULTS
  Synovial tissue samples were obtained by arthroscopy from 62 RA patients before the initiation of infliximab treatment. RNA was extracted and gene expression profiling was performed using an in-house spotted long oligonucleotide array covering 17972 unique genes. Tissue sections were also analyzed by immunohistochemistry to evaluate cell infiltrates. Response to infliximab treatment was assessed according to the EULAR response criteria. The presence of lymphocyte aggregates dominated the expression profiles and a significant overrepresentation of lymphocyte aggregates in good responding patients confounded the analyses. A statistical model was set up to control for the effect of aggregates, but no differences could be identified between responders and non-responders. Subsequently, the patients were split into lymphocyte aggregate positive- and negative patients. No statistically significant differences could be identified except for 38 transcripts associated with differences between good- and non-responders in aggregate positive patients. A profile was identified in these genes that indicated a higher level of metabolism in good responding patients, which indirectly can be connected to increased inflammation.
  
  
  CONCLUSIONS
  It is pivotal to account for the presence of lymphoid aggregates when studying gene expression patterns in rheumatoid synovial tissue. In spite of our original hypothesis, the data do not support the notion that microarray analysis of whole synovial biopsy specimens can be used in the context of personalized medicine to identify non-responders to anti-TNF therapy before the initiation of treatment.
authors.affiliation: Department of Gene Technology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Carla A
authors.initials: CA
authors.lastname: Wijbrandts
authors.forename: Lisa G
authors.initials: LG
authors.lastname: van Baarsen
authors.forename: Gustavo
authors.initials: G
authors.lastname: Nader
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Anca
authors.initials: A
authors.lastname: Catrina
authors.forename: Rogier
authors.initials: R
authors.lastname: Thurlings
authors.forename: Margriet
authors.initials: M
authors.lastname: Vervoordeldonk
authors.forename: Joakim
authors.initials: J
authors.lastname: Lundeberg
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D001706:Biopsy; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab