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Objective RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. Methods RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. Results At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. Conclusion Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Objective To investigate the pathologic nature of features termed “bone erosion” and “bone marrow edema” (also called “osteitis) on magnetic resonance imaging (MRI) scans of joints affected by rheumatoid arthritis (RA). Methods RA patients scheduled for joint replacement surgery (metacarpophalangeal or proximal interphalangeal joints) underwent MRI on the day before surgery. The presence and localization of bone erosions and bone marrow edema as evidenced by MRI (MRI bone erosions and MRI bone marrow edema) were documented in each joint (n = 12 joints). After surgery, sequential sections from throughout the whole joint were analyzed histologically for bone marrow changes, and these results were correlated with the MRI findings. Results MRI bone erosion was recorded based on bone marrow inflammation adjacent to a site of cortical bone penetration. Inflammation was recorded based on either invading synovial tissue (pannus), formation of lymphocytic aggregates, or increased vascularity. Fat-rich bone marrow was replaced by inflammatory tissue, increasing water content, which appears as bright signal enhancement on STIR MRI sequences. MRI bone marrow edema was recorded based on the finding of inflammatory infiltrates, which were less dense than those of MRI bone erosions and localized more centrally in the joint. These lesions were either isolated or found in contact with MRI bone erosions. Conclusion MRI bone erosions and MRI bone marrow edema are due to the formation of inflammatory infiltrates in the bone marrow of patients with RA. This emphasizes the value of MRI in sensitively detecting inflammatory tissue in the bone marrow and demonstrates that the inflammatory process extends to the bone marrow cavity, which is an additional target structure for antiinflammatory therapy.

Objective To determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). Methods Patients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. Results Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. Conclusion Etanercept is a highly effective and well tolerated treatment in patients with active AS.