Ultrasound of MCPJs for Drug Therapies in RA
Ultrasound of MCPJs for Drug Therapies in RA
Introduction We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).
Methods A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15mg or 7.5mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP).
Results All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures.
Conclusions Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy.
Trial Registration Clinicaltrials.gov identifier: NCT00746512
The development of new therapeutics for rheumatoid arthritis (RA) involves clinical assessment of response by endpoints that include composite measures of disease activity, such as the Disease Activity Score in 28 Joints (DAS28), a continuous measure, and American College of Rheumatology (ACR) categorical responses. Many of the component measurements are subjective, imprecise and insensitive to change and their use often necessitates lengthy and costly clinical trials using large cohorts of patients. This results in greater exposure to experimental drugs in early testing, many of which will eventually fail to receive approval.
For early testing of novel therapeutics, we require a sensitive method to distinguish between treatment groups in cohort studies that permits small patient numbers and provides a reliable, early indicator of efficacy. Ideally, such measures would be quick, non-invasive, objective, predict longer-term response to repeated medication and give an early indication of disease modification. Due to ethical constraints of performing placebo controlled trials and the resultant trend towards comparator controlled trials, the requirement for sensitive endpoints is greater than ever.
Metacarpophalangeal joints (MCPJs) are invariably involved in RA and so their evaluation is important. These superficial joints are amenable to assessment with ultrasound (US) utilizing frequencies that produce high resolution images. High-frequency ultrasonography (HFUS) and power Doppler ultrasonography (PDUS) are reproducible tools for determining synovitis and more sensitive than clinical scoring in determining disease activity. The synovial vascular signal on PDUS closely correlates with the dynamic contrast enhanced magnetic resonance imaging (MRI) in RA MCPJs and synovitis detected by US predicts erosive disease.
Abstract and Introduction
Abstract
Introduction We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).
Methods A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15mg or 7.5mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP).
Results All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures.
Conclusions Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy.
Trial Registration Clinicaltrials.gov identifier: NCT00746512
Introduction
The development of new therapeutics for rheumatoid arthritis (RA) involves clinical assessment of response by endpoints that include composite measures of disease activity, such as the Disease Activity Score in 28 Joints (DAS28), a continuous measure, and American College of Rheumatology (ACR) categorical responses. Many of the component measurements are subjective, imprecise and insensitive to change and their use often necessitates lengthy and costly clinical trials using large cohorts of patients. This results in greater exposure to experimental drugs in early testing, many of which will eventually fail to receive approval.
For early testing of novel therapeutics, we require a sensitive method to distinguish between treatment groups in cohort studies that permits small patient numbers and provides a reliable, early indicator of efficacy. Ideally, such measures would be quick, non-invasive, objective, predict longer-term response to repeated medication and give an early indication of disease modification. Due to ethical constraints of performing placebo controlled trials and the resultant trend towards comparator controlled trials, the requirement for sensitive endpoints is greater than ever.
Metacarpophalangeal joints (MCPJs) are invariably involved in RA and so their evaluation is important. These superficial joints are amenable to assessment with ultrasound (US) utilizing frequencies that produce high resolution images. High-frequency ultrasonography (HFUS) and power Doppler ultrasonography (PDUS) are reproducible tools for determining synovitis and more sensitive than clinical scoring in determining disease activity. The synovial vascular signal on PDUS closely correlates with the dynamic contrast enhanced magnetic resonance imaging (MRI) in RA MCPJs and synovitis detected by US predicts erosive disease.
To investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints (quantitative and semi-quantitative measures of synovial thickness and vascularity in MCPJs imaged in the dorsal longitudinal and transverse planes) and make comparisons between different endpoints. We have investigated the reliability of a summation of 10 MCPJs rather than the reliability on a joint by joint basis.
To determine the potential of two-dimensional ultrasonographic endpoints to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).
To determine if there is a dose-response relationship between the two different relatively low, corticosteroid doses (15 mg and 7.5 mg) and ultrasonographic endpoints.
To compare the US endpoints with DAS28(CRP) (C-reactive protein) and to explore the potential of composite endpoints (DAS28 combined with US endpoints) to improve the registration of a significant treatment effect.
