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; ClinicalTrials.gov number, NCT00665925.)