Investigation of the role of articular ultrasonography in rheumatoid arthritis early phase clinical trials

Objective To investigate the utility of ultrasonographic measures of synovitis in rheumatoid arthritis (RA) early phase clinical trials. Methods Study 1 contained a double-blind, placebo and comparator controlled two-centre study to investigate the effect of 28 days repeat daily oral dosing of 60 mg of an inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. 50 subjects (DAS28≥4.0) were randomized into 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial vascularity was assessed in the transverse plane over the dorsum of all 10 metacarpophalangeal joints (MCPJs) by ultrasonography and measured quantitatively as power Doppler area (PDA). Study 2 was a randomized, double-blind, parallel group, placebo controlled two-centre study to assess the effects of oral prednisone (15 mg once daily) on DAS28(CRP) and ultrasonographic measures of MCPJ synovitis (quantitative and qualitative assessments of synovial vascularity and thickness measured in the longitudinal and transverse planes over the dorsum) in 18 subjects (10 placebo and 8 prednisone) with RA (DAS28≥3.2) over 2 weeks; endpoints measured on Day 1 (baseline), Day 2, Day 8 and Day 15. Results Study 1: At Day 28, there was a 55% decrease in PDA for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). Study 2: In the prednisone group significant treatment effects were observed at all time points for a variety of US endpoints (largest effect size=1.82) but only at Day 15 for DAS28(CRP) (effect size=0.95, P=0.032). The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of ultrasound measures. Conclusion Ultrasonography of MCPJs could be utilized in early phase RA clinical trials to reduce patient numbers and trial length. Key words: Rheumatoid Arthritis Ultrasound Power Doppler Ultrasound Gray-Scale Ultrasound Corticosteroid Prednisolone Prednisone GW274150 iNOS (inducible nitric oxide synthase) Metacarpophalangeal Joints Synoviti