Titre du document / Document title

Treatment of Rheumatoid Arthritis With a Syk Kinase Inhibitor : A Twelve-Week, Randomized, Placebo-Controlled Trial

Auteur(s) / Author(s)

WEINBLATT Michael E. ⁽¹⁾ ; KAVANAUGH Arthur ⁽²⁾ ; BURGOS-VARGAS Ruben ⁽³⁾ ; DIKRANIAN Ara H. ⁽⁴⁾ ; MEDRANO-RAMIREZ Gabriel ⁽⁵⁾ ; MORALES-TORRES Jorge L. ⁽⁶⁾ ; MURPHY Frederick T. ⁽⁷⁾ ; MUSSER Theresa Kane ⁽⁸⁾ ; STRANIERO Nicholas ⁽⁹⁾ ; VICENTE-GONZALES Angela V. ⁽¹⁰⁾ ; GROSSBARD Elliott ⁽⁸⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, ETATS-UNIS
⁽²⁾ University of California, San Diego, ETATS-UNIS
⁽³⁾ Hospital General de Mexico, Mexico City, MEXIQUE
⁽⁴⁾ San Diego Arthritis Medical Clinic, San Diego, California, ETATS-UNIS
⁽⁵⁾ Clinica para el Diagnostico y Tratamiento de las Enfermedadas Reumaticas, Mexico City, MEXIQUE
⁽⁶⁾ Jorge L. Morales-Torres, MD: Hospital Aranda de la Parra, Guanajauto, MEXIQUE
⁽⁷⁾ Altoona Center for Clinical Research, North Duncansville, Pennsylvania, ETATS-UNIS
⁽⁸⁾ Rigel, South San Francisco, California, ETATS-UNIS
⁽⁹⁾ Memorial Medical Group, South Bend, Indiana, ETATS-UNIS
⁽¹⁰⁾ Arke Estudios Clinicos, Mexico City, MEXIQUE

Résumé / Abstract

Objective. Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ-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.

Revue / Journal Title

Arthritis and rheumatism   ISSN 0004-3591   CODEN ARHEAW 

Source / Source

2008, vol. 58, n^o11, pp. 3309-3318 [10 page(s) (article)] (19 ref.)

Langue / Language

Anglais

Editeur / Publisher

Wiley, Hoboken , NJ, ETATS-UNIS  (1958) (Revue)

Mots-clés anglais / English Keywords

Immunopathology ; Diseases of the osteoarticular system ; Inflammatory joint disease ; Autoimmune disease ; Enzyme ; Transferases ; Chronic ; Rheumatology ; Kinase ; Treatment ; Rheumatoid arthritis ;

Mots-clés français / French Keywords

Immunopathologie ; Pathologie du système ostéoarticulaire ; Rhumatisme inflammatoire ; Maladie autoimmune ; Enzyme ; Transferases ; Chronique ; Rhumatologie ; Kinase ; Traitement ; Polyarthrite rhumatoïde ;

Mots-clés espagnols / Spanish Keywords

Inmunopatología ; Sistema osteoarticular patología ; Reumatismo inflamatorio ; Enfermedad autoinmune ; Enzima ; Transferases ; Crónico ; Reumatología ; Kinase ; Tratamiento ; Poliartritis reumatoidea ;

Localisation / Location

INIST-CNRS, Cote INIST : 8711, 35400018430679.0050