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Objective To examine the efficacy of methotrexate monotherapy relative to etanercept monotherapy and the value of combining methotrexate and etanercept for the treatment of patients with psoriatic arthritis (PsA). Methods In this double-blind study, 851 patients with PsA were randomized to 1 of 3 treatment arms, as follows: oral methotrexate (20 mg) plus subcutaneous placebo given weekly (n = 284), subcutaneous etanercept (50 mg) plus oral placebo given weekly (n = 284), or subcutaneous etanercept (50 mg) plus oral methotrexate (20 mg) given weekly (combination therapy; n = 283). The American College of Rheumatology 20% improvement (ACR20) response and Minimal Disease Activity (MDA) response at week 24 were the primary end point and key secondary end point, respectively. Other measures of inflammatory arthritis, radiographic progression, and nonarticular disease manifestations were also assessed. Results Patients with PsA had a mean ± SD age of 48.4 ± 13.1 years, and the mean ± SD duration of PsA was 3.2 ± 6.3 years (median 0.6 years). ACR20 and MDA response rates at week 24 were significantly greater in patients who received etanercept monotherapy compared with those who received methotrexate monotherapy (ACR20, 60.9% versus 50.7% of patients [P = 0.029]; MDA, 35.9% versus 22.9% of patients [P = 0.005]), and both were significantly greater in the combination therapy group compared with the methotrexate monotherapy group at week 24 (ACR20, 65.0% versus 50.7% of patients [P = 0.005]; MDA, 35.7% versus 22.9% of patients [P = 0.005]). Other secondary outcomes (ACR50 and ACR70 response rates, proportions of patients achieving a Very Low Disease Activity score, and PsA disease activity scores) showed between-group differences that were consistent with the primary and key secondary end point results. Furthermore, patients in both etanercept treatment arms showed less radiographic progression at week 48 compared with patients who received methotrexate monotherapy. Outcomes were similar in the combination therapy and etanercept monotherapy groups, except for some skin end points. No new safety signals were seen. Conclusion Etanercept monotherapy and combination therapy with etanercept and methotrexate showed greater efficacy than methotrexate monotherapy in patients with PsA, according to the ACR and MDA response rates and extent of radiographic progression at follow-up. Overall, combining methotrexate and etanercept did not improve the efficacy of etanercept.

Introduction Etanercept, a tumor necrosis factor inhibitor, is used to treat rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and is administered via subcutaneous injection. Injection site pain (ISP) associated with subcutaneous administration may affect compliance or hinder initiation of prescribed medications. To improve the patient experience, a new phosphate-free formulation of etanercept was evaluated for reduced ISP associated with administration. Methods This phase 3b, multicenter, randomized, double-blind, cross-over study compared the prior formulation of etanercept to a phosphate-free formulation. Etanercept-naïve adults with RA or PsA indicated for treatment with etanercept were eligible. Patients were randomized (1:1) to receive both etanercept formulations (50 mg) in one of two crossover sequences: prior formulation followed by phosphate-free formulation (sequence AB) or phosphate-free formulation followed by prior formulation (sequence BA) at visits 1 week apart. Patients self-reported ISP using a fit-for-purpose 100-mm visual analog scale within 30 s after injection. Safety outcomes included incidence of treatment-emergent adverse events. Mixed-effects analysis of variance model was used to assess ISP, with treatment, study period, sequence, and disease indication as fixed-effect covariates and patient-within-sequence as random effect. Results A total of 111 patients enrolled (56 sequence AB; 55 sequence BA). Mean ISP score for prior formulation was 23.1 mm and for phosphate-free formulation was 19.1 mm (mean difference − 4 mm; 95% confidence interval: − 8.0, 0.0; P = 0.048). Patients with the highest ISP scores from the prior formulation (by quartile cut points) had the largest reduction in pain with phosphate-free formulation. Injection site reactions were few in number and similar between formulations; no new safety signals were observed. Conclusions The new phosphate-free formulation of etanercept had statistically significantly lower mean pain scores than the prior formulation, with largest pain reductions observed among patients who reported highest pain with the prior formulation. Trial Registration ClinicalTrials.gov: NCT02986139. Funding Amgen Inc, Thousand Oaks, CA USA.

Objectives To examine which composite measures are most sensitive to change when measuring psoriatic arthritis (PsA) disease activity, analyses compared the responsiveness of composite measures used in a 48-week randomized, controlled trial of MTX and etanercept in patients with PsA. Methods The trial randomised 851 patients to receive weekly: MTX (20 mg/week), etanercept (50 mg/week) or MTX plus etanercept. Dichotomous composite measures examined included ACR 20/50/70 responses, minimal disease activity (MDA) and very low disease activity (VLDA). Continuous composite measures examined included Disease Activity Score (28 joints) using CRP (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS). Results At week 24, etanercept-treated groups were significantly more effective than MTX monotherapy to achieve ACR 20 (primary end point) and MDA (key secondary end point). When examining score changes from baseline at week 24 across the five continuous composite measures, PASDAS demonstrated relatively greater changes in the etanercept-treated groups compared with MTX monotherapy and had the largest effect size and standardized response. Joint count changes drove overall score changes at week 24 from baseline in all the continuous composite measures except for PASDAS, which was driven by the Physician and Patient Global Assessments. Conclusion PASDAS was the most sensitive continuous composite measure examined with results that mirrored the protocol-defined primary and key secondary outcomes. Composite measures with multiple domains, such as PASDAS, may better quantify change in PsA disease burden. Trail registration https://ClinicalTrials.gov, number NCT02376790.

Objective To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. Methods In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. Conclusion AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Objectives To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose and multiple-dose administration of AMG 557, a human anti-inducible T cell co-stimulator ligand (ICOSL) monoclonal antibody, in subjects with systemic lupus erythematosus (SLE). Methods Patients with mild, stable SLE (n=112) were enrolled in two clinical trials to evaluate the effects of single (1.8–210 mg subcutaneous or 18 mg intravenous) and multiple (6 –210 mg subcutaneous every other week (Q2W)×7) doses of AMG 557. Subjects received two 1 mg intradermal injections 28 days apart of keyhole limpet haemocyanin (KLH), a neoantigen, to assess PD effects of AMG 557. Safety, PK, target occupancy, anti-KLH antibody responses, lymphocyte subset analyses and SLE-associated biomarkers and clinical outcomes were assessed. Results AMG 557 demonstrated an acceptable safety profile. The PK properties were consistent with an antibody directed against a cell surface target, with non-linear PK observed at lower concentrations and linear PK at higher concentrations. Target occupancy by AMG 557 was dose dependent and reversible, and maximal occupancy was achieved in the setting of this trial. Anti-AMG 557 antibodies were observed, but none were neutralising and without impact on drug levels. A significant reduction in the anti-KLH IgG response was observed with AMG 557 administration without discernible changes in the anti-KLH IgM response or on the overall IgG levels. No discernible changes were seen in lymphocyte subsets or in SLE-related biomarkers and clinical measures. Conclusions The selective reduction in anti-KLH IgG demonstrates a PD effect of AMG 557 in subjects with SLE consistent with the biology of the ICOS pathway and supports further studies of AMG 557 as a potential therapeutic for autoimmune diseases. Trial registration numbers NCT02391259 and NCT00774943.

Introduction The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA). Methods This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥6/66 swollen and ≥8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics. Results Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70. Conclusions Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA. Trial registration ClinicalTrials.gov, NCT00771030