Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial

Arthritis Rheum. 2008 Nov;58(11):3309-18. doi: 10.1002/art.23992.


Objective: Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcgamma-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA).

Methods: We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.

Results: Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related.

Conclusion: These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aminopyridines
  • Arthritis, Rheumatoid / drug therapy*
  • Double-Blind Method
  • Humans
  • Interleukin-6 / blood
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Male
  • Matrix Metalloproteinase 3 / blood
  • Methotrexate / therapeutic use
  • Middle Aged
  • Morpholines
  • Oxazines / administration & dosage
  • Oxazines / adverse effects
  • Oxazines / therapeutic use*
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Prodrugs / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyridines / administration & dosage
  • Pyridines / adverse effects
  • Pyridines / therapeutic use*
  • Pyrimidines
  • Syk Kinase


  • Aminopyridines
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Oxazines
  • Prodrugs
  • Pyridines
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Matrix Metalloproteinase 3
  • fostamatinib
  • Methotrexate