Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.
BACKGROUND
Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis.


METHODS
In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548.


RESULTS
The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.


CONCLUSIONS
Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis.


BACKGROUND
F Hoffmann-La Roche, Chugai Pharmaceutical.
Smolen
Josef S
JS
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. josef.smolen@meduniwien.ac.at
Beaulieu
Andre
A
Rubbert-Roth
Andrea
A
Ramos-Remus
Cesar
C
Rovensky
Josef
J
Alecock
Emma
E
Woodworth
Thasia
T
Alten
Rieke
R
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000145:classification / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab