Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis.

OBJECTIVE: Osteoclast-mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer-based technique, digital x-ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA. METHODS: Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer-assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands. RESULTS: At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: -0.0034, denosumab 180 mg: 0.0001 gain, placebo: -0.0108; P < or = 0.01 for both denosumab doses). Twelve-month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio. CONCLUSION: Twice-yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.

Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial.

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.

Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial.

OBJECTIVE: To evaluate the efficacy and safety of treatment with adalimumab, a fully human anti-tumor necrosis factor (anti-TNF) monoclonal antibody, over 48 weeks in patients with moderate to severe psoriatic arthritis (PsA). METHODS: Patients who completed the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), a 24-week, double-blind study of adalimumab versus placebo in PsA, could elect to receive open-label adalimumab, 40 mg subcutaneously every other week after week 24. Radiographs were obtained at week 48 and were read with radiographs obtained previously. Clinical and radiographic efficacy data were analyzed overall and in patient subsets. Safety data were collected over 48 weeks. RESULTS: At week 48, patients from the adalimumab arm of ADEPT (n = 151) had achieved American College of Rheumatology 20% improvement (ACR20), ACR50, and ACR70 response rates of 56%, 44%, and 30%, respectively. Among those evaluated with the Psoriasis Area and Severity Index (PASI) (n = 69), PASI50, PASI75, PASI90, and PASI100 response rates (> or =50%, > or =75%, > or =90%, and 100% reduction in PASI scores, respectively) were 67%, 58%, 46%, and 33%, respectively (ACR and PASI response rates were analyzed using nonresponder imputation). Improvements in disability, as measured by the Disability Index of the Health Assessment Questionnaire (mean change in score -0.4) were sustained from week 24 to week 48. At week 24 and week 48, the mean changes from baseline in the modified total Sharp score were -0.1 and 0.1, respectively, for patients who received adalimumab for 48 weeks (n = 133), and 0.9 and 1.0, respectively, for patients who received placebo for 24 weeks followed by adalimumab for 24 weeks (n = 141). Adalimumab demonstrated clinical and radiographic efficacy regardless of whether patients were receiving methotrexate (MTX) at baseline. Adalimumab was generally safe and well tolerated through week 48. CONCLUSION: Adalimumab improved joint and skin manifestations, reduced disability, and inhibited radiographic progression over 48 weeks in patients with PsA who were participants in ADEPT. MTX use at baseline was not required for clinical or radiographic efficacy. Adalimumab had a good safety profile through week 48.

Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept.

OBJECTIVE: Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept. METHODS: Patients were previously randomized to receive placebo or etanercept in a double-blind study and chose to participate in the current open-label extension phase. All patients received etanercept 25 mg twice weekly. Radiographic progression was determined at baseline, 1 year, and 2 years using the Sharp method modified to include joints frequently affected in PsA. Arthritis and psoriasis responses were determined using American College of Rheumatology 20% (ACR20) improvement criteria, PsA response criteria (PsARC), and the psoriasis area severity index (PASI). RESULTS: Of 205 patients randomized, 169 entered open-label, and 141 [71 randomized to receive placebo (placebo/etanercept) and 70 randomized to receive etanercept (etanercept/etanercept)] had radiographic data available for analysis at 2 years. ACR20 criteria, PsARC, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of etanercept/etanercept patients at the end of the 48-week open-label period. Placebo/etanercept patients achieved comparable results within 12 weeks that were sustained at 48 weeks (63%, 80%, and 73%). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 yrs). In placebo/etanercept patients, disease progression was inhibited once patients began receiving etanercept (mean adjusted change of -0.22 from 1 year to 2 years). Adverse event rates were similar to those observed during randomized phase, with only one serious adverse event deemed possibly related to etanercept. CONCLUSION: These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). METHODS: Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. RESULTS: At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. CONCLUSION: Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.

Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression.

OBJECTIVE: Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA. METHODS: Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase, then could receive open-label etanercept in a 48-week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12-week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open-label phase, and after 48 weeks in the study. RESULTS: Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated. CONCLUSION: Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA.

Radiography in the assessment of musculoskeletal conditions.

Plain film radiography is the most widely used imaging technique for diagnosing and monitoring the progression of chronic inflammatory and degenerative joint diseases. Advanced imaging techniques that are better suited for detecting soft-tissue inflammation are available, but they are more costly and some of them may expose the patient to higher doses of radiation. Plain film radiographs are inexpensive, easy to generate, can be compared with baseline and prospective films, and provide a permanent, reproducible record. Radiographs can easily detect the features that are specific to various rheumatological disorders, and serial radiography can be used to assess response to therapy by measuring erosions, joint space narrowing, and other disease-specific features. This chapter discusses the use of radiography for diagnosing and differentiating various rheumatic joint diseases, specifically rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and osteoarthritis. The most frequently used scoring systems that are used to assess and monitor the severity and progression of these disorders are briefly described.