title: Methotrexate and a spleen tyrosine kinase inhibitor cooperate to inhibit responses to peripheral blood B cells in rheumatoid arthritis.
abstract: BACKGROUND
  Selective disruption of the spleen tyrosine kinase (Syk) represents a novel strategy to control B-cell functional responses by inhibition of B-cell antigen receptor (BCR) signaling. PRT062607 (P505-15) is a highly selective small molecule Syk inhibitor that potently suppresses B-cell function in human and rodent blood, and reduces inflammation in rodent models of rheumatoid arthritis (RA).
  
  
  OBJECTIVE
  In this study, we sought to determine the potency of Syk inhibition by PRT062607 in whole blood from RA patients, and elucidate covariates that affect the potency of immune-regulation by this compound.
  
  
  METHODS
  Whole blood was collected from 30 patients diagnosed with RA as part of a single-center outpatient study. Disease severity, serum protein markers of inflammation, and co-medications were related to each other, and to PRT062607 activity in ex vivo Syk-mediated immune function assays.
  
  
  RESULTS
  We report here that PRT062607 exhibited greater potency in suppressing BCR mediated B-cell functional responses in whole blood from RA patients who received stable methotrexate (MTX) therapy. We demonstrate that the B-cell functional response to BCR ligation is influenced by cytokines and JAK/STAT signaling.
  
  
  CONCLUSIONS
  MTX is a known cytokine modulating agent, and this mechanism may act in concert with PRT062607 to control B-cell function.
  
  
  CONCLUSIONS
  These data have important implications for the co-administration of Syk inhibitors and MTX for the treatment of RA.
authors.affiliation: Portola Pharmaceuticals, Inc. South San Francisco, California, 94080.
authors.forename: Greg
authors.initials: G
authors.lastname: Coffey
authors.affiliation: Portola Pharmaceuticals, Inc. South San Francisco, California, 94080.
authors.forename: Andreas
authors.initials: A
authors.lastname: Betz
authors.affiliation: University of California San Francisco, School of Medicine San Francisco, California, 94143.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Graf
authors.affiliation: Portola Pharmaceuticals, Inc. South San Francisco, California, 94080.
authors.forename: Gillian
authors.initials: G
authors.lastname: Stephens
authors.affiliation: Portola Pharmaceuticals, Inc. South San Francisco, California, 94080.
authors.forename: Pei
authors.initials: P
authors.lastname: Hua Lin
authors.affiliation: University of California San Francisco, School of Medicine San Francisco, California, 94143.
authors.forename: John
authors.initials: J
authors.lastname: Imboden
authors.affiliation: Portola Pharmaceuticals, Inc. South San Francisco, California, 94080.
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
keywords: B cells; methotrexate; rheumatoid arthritis; spleen tyrosine kinase