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Methotrexate and a Spleen Tyrosine Kinase Inhibitor Cooperate to Inhibit Responses to Peripheral Blood B Cells in Rheumatoid Arthritis

Methotrexate and a Spleen Tyrosine Kinase Inhibitor Cooperate to Inhibit Responses to Peripheral Blood B Cells in Rheumatoid Arthritis

Greg Coffey, Andreas Betz, Jonathan Graf, Gillian Stephens, Pei Hua Lin, John Imboden, Uma Sinha

Pharmacol Res Perspect. 2013 Dec;1(2):e00016.

PMID: 25505569

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).
Aims:
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.
Materials and 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.
Discussion:
MTX is a known cytokine modulating agent, and this mechanism may act in concert with PRT062607 to control B-cell function.
Conclusion:
These data have important implications for the co-administration of Syk inhibitors and MTX for the treatment of RA.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54626-A	Methotrexate Related Compound B		54-62-6	Price

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