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 Other Agents2120. RANKL Inhibition with Denosumab Reduces Progression of Bone Erosions in Patients with Rheumatoid Arthritis: Month 6 MRI ResultsAuthors: SB Cohen, P Valen, C Ritchlin, J Schechtman, C Peterfy, D van der Heijde, L Zhou, R Newmark, W Tsuji. BACKGROUND: The receptor activator of NF-kB ligand (RANKL) is critically involved in the activation and differentiation of osteoclasts and involved in bone resorption in osteoporosis, metastatic bone disease, and rheumatoid arthritis. Denosumab (previously AMG 162) is a fully human, monoclonal antibody that inhibits RANKL and has been shown to be efficacious in osteoporosis treatment. Given its potent effects on osteoclasts, this study was designed to assess whether the drug would affect bony erosions in patients with RA. Given the increased sensitivity for MRI to potentially evaluate bony changes in a shorter period of time than plain radiographs, and given the newly developed scoring system for assessing MRI changes in RA provided the opportunity to evaluate this as an additional outcome in a study of denosumab in RA progression. METHODS: This was a double-blind, placebo-controlled study of 227 patients with mild to moderately active RA with baseline erosions or with elevated CRP and anti CCP antibodies, who were maintained on methotrexate (7.5-25 mg/wk), though steroids (< 15 mg/d), biologic therapy, HCQ, SSZ, and bisphosphonates were also allowed. Patients were randomly assigned to treatment with subcutaneous injections of denosumab (60 or 180 mg) or placebo (PBO) given every 6 months but were stratified by biologic use past and current. A 1.5 Tesla MRI was obtained without contrast. RA-MRI erosion scores (RAMRIS) for both hands (MCP) and both wrists were determined at baseline and month 6 (erosion score 500 max, osteitis score 150 max) using with readers blinded to treatment and sequence. Plain radiographs of both hands and both feet were taken at baseline and month 6 and will be taken at month 12; radiographs remain blinded. Safety was monitored throughout the study. RESULTS: Baseline demographic and disease activity parameters were generally balanced between groups. Most patients were female (73%), with a mean age 57.4 and disease duration of 11 years. The baseline MRI erosion score was lower in the PBO group than denosumab groups (32, 42, and 45 for PBO, 60-mg, and 180-mg groups). Patients in the denosumab 180-mg group had significantly less progression of bone erosions than the PBO group at 6 months (P<0.019), as determined by MRI. Progression of the MRI erosion score was also numerically less in the denosumab 60-mg group than PBO (P=0.247). IA larger proportion of patients in the PBO group had an increase in MRI erosion score from baseline to 6 months than either denosumab dose group (53%, 42%, 30% in the PBO, 60-mg, and 180-mg groups, respectively [P=0.01 for 180-mg group vs PBO]). No significant differences among treatment groups were seen for change in MRI osteitis (bone edema) or measures of RA disease activity (ACR score or DAS) at 6 months. Adverse events (AEs) occurred with similar frequency in the denosumab and PBO dose groups. CONCLUSION: RANKL inhibition with a single dose of 180 mg denosumab significantly reduced progression of bone erosions as assessed by MRI at 6 months compared with PBO, with a similar AE profile. EDITORIAL COMMENT: This study provides very exciting information regarding the use of a potent osteoclast inhibitor in patients with RA. Given the growing knowledge of the role of the osteoclast in medicating bone destruction in both RA as well as in Psoriatic arthritis, the possibility of an agent that specifically targets the osteoclast to have an impact on this process specifically is a welcome addition to the treatment armamentarium. It is unclear however whether this agent would necessarily have an effect on cartilage degradation and joint space loss. It is unclear whether the acquisition parameters captured information that would allow further assessment of cartilage thickness or volume. That the agent has not shown significant untoward adverse events is also encouraging. It is perhaps not surprising however that there was no effect seen on signs and symptoms with the agent. The use of the MRI and the RAMRIS scoring system to show the short term changes is also novel and will need to be correlated with the longer term plain radiographic results that will be forthcoming from this study. Where this compound would ultimately place in the treatment of RA is unclear but one could envision treatment early in disease to inhibit erosions while other DMARDS were instituted as well as later in disease as more toxic DMARDS were tapered after achieving an initial clinical response in order to continue to prevent disease progression. Studying this compound in conjunction with other background DMARD medications however will likely require some revision of traditional study designs and outcomes to allow the individual contribution of this drug to be assessed.
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