An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis

N Engl J Med. 2010 Sep 30;363(14):1303-12. doi: 10.1056/NEJMoa1000500. Epub 2010 Sep 22.


Background: Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy.

Methods: We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6.

Results: R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy.

Conclusions: In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; number, NCT00665925.)

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopyridines
  • Antirheumatic Agents / adverse effects
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Male
  • Methotrexate / therapeutic use
  • Middle Aged
  • Morpholines
  • Oxazines / adverse effects
  • Oxazines / therapeutic use*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Pyrimidines
  • Statistics, Nonparametric
  • Syk Kinase
  • Treatment Outcome


  • Aminopyridines
  • Antirheumatic Agents
  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Oxazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • fostamatinib
  • Methotrexate

Associated data