Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial.
Arthritis Rheum
; 58(11): 3309-18, 2008 Nov.
Article
en En
| MEDLINE
| ID: mdl-18975322
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_diarrhea
Asunto principal:
Oxazinas
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Artritis Reumatoide
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Piridinas
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Proteínas Tirosina Quinasas
/
Profármacos
/
Péptidos y Proteínas de Señalización Intracelular
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Adult
/
Aged
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Arthritis Rheum
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos