title: Differential gene expression profiles may differentiate responder and nonresponder patients with rheumatoid arthritis for methotrexate (MTX) monotherapy and MTX plus tumor necrosis factor inhibitor combined therapy.
abstract: OBJECTIVE
  We aimed to evaluate whether the differential gene expression profiles of patients with rheumatoid arthritis (RA) could distinguish responders from nonresponders to methotrexate (MTX) and, in the case of MTX nonresponders, responsiveness to MTX plus anti-tumor necrosis factor-α (anti-TNF) combined therapy.
  
  
  METHODS
  We evaluated 25 patients with RA taking MTX 15-20 mg/week as a monotherapy (8 responders and 17 nonresponders). All MTX nonresponders received infliximab and were reassessed after 20 weeks to evaluate their anti-TNF responsiveness using the European League Against Rheumatism response criteria. A differential gene expression analysis from peripheral blood mononuclear cells was performed in terms of hierarchical gene clustering, and an evaluation of differentially expressed genes was performed using the significance analysis of microarrays program.
  
  
  RESULTS
  Hierarchical gene expression clustering discriminated MTX responders from nonresponders, and MTX plus anti-TNF responders from nonresponders. The evaluation of only highly modulated genes (fold change > 1.3 or < 0.7) yielded 5 induced (4 antiapoptotic and CCL4) and 4 repressed (4 proapoptotic) genes in MTX nonresponders compared to responders. In MTX plus anti-TNF non-responders, the CCL4, CD83, and BCL2A1 genes were induced in relation to responders.
  
  
  CONCLUSIONS
  Study of the gene expression profiles of RA peripheral blood cells permitted differentiation of responders from nonresponders to MTX and anti-TNF. Several candidate genes in MTX non-responders (CCL4, HTRA2, PRKCD, BCL2A1, CAV1, TNIP1, CASP8AP2, MXD1, and BTG2) and 3 genes in MTX plus anti-TNF nonresponders (CCL4, CD83, and BCL2A1) were identified for further study.
authors: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil. reneimuno@yahoo.com.br
authors: Renê Donizeti Ribeiro
authors: RD
authors: Oliveira
authors: Vanessa
authors: V
authors: Fontana
authors: Cristina Moraes
authors: CM
authors: Junta
authors: Márcia Maria Chiquitelli
authors: MM
authors: Marques
authors: Cláudia
authors: C
authors: Macedo
authors: Diane Meyre
authors: DM
authors: Rassi
authors: Geraldo Aleixo
authors: GA
authors: Passos
authors: Eduardo Antonio
authors: EA
authors: Donadi
authors: Paulo
authors: P
authors: Louzada-Junior
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*; D004359:Drug Therapy, Combination; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D000069285:Infliximab; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D059467:Transcriptome; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D008727:Methotrexate