A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.

OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.

Relation between fibrositic and control site tenderness; effects of dolorimeter scale length and footplate size.

Recent data have suggested a correlation between the tenderness measured at tender and control sites, differing from earlier studies indicating site specific tenderness. In our study, the "constant control" model is tested against the "correlated control" model, in which control site tenderness varies with fibrositic site tenderness. Our study also addresses relevant technical issues in dolorimetry. We measured threshold of tenderness at 4 sites (2 fibrositic and 2 control) on 21 subjects, using dolorimeters with a 17 kg scale limit, and 3 different footplates, 0.7, 1.4 and 2.0 cm in diameter. To measure observer variation, we used multiple replications by multiple observers, obtaining in all 1,416 observations. There was a strong relationship between control and fibrositic site tenderness with control thresholds twice as high (half as tender). Scale length and dolorimeter footplate size each had important effects. The site specific approach is valuable diagnostically, but more broadly operative mechanisms should be the focus of research and therapy.