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Objective Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination. Methods Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24‐week open‐label period. These 253 patients then entered a 48‐week, double‐blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease‐worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run‐in period. The primary end point was the proportion of patients in whom SDAI‐defined remission was maintained without disease‐worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease‐worsening, and the proportion of patients in whom SDAI‐defined remission was recaptured after initiation of rescue therapy. Results Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI‐defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI‐defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease‐worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI‐defined remission was recaptured in 70–80% in each treatment group. No new safety signals were reported. Conclusion The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI‐defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision‐making when withdrawal of therapy is being considered to reduce treatment burden in patients with well‐controlled RA.

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.

Neil A Accortt,1 James B Chung,2 Machaon Bonafede,3 Brendan L Limone,3 David M Mannino4 1Amgen, Inc., Center for Observational Research, Thousand Oaks, CA, 2Amgen, Inc., US Medical Organization, Thousand Oaks, CA, 3Truven Health Analytics, an IBM Company, Outcomes Research, Cambridge, MA, 4University of Kentucky College of Public Health, Lexington, KY, USA Background: Limited information exists on the impact of tumor necrosis factor inhibition on COPD exacerbations. This retrospective study characterized this impact among COPD patients with underlying autoimmune conditions, exposed to tumor necrosis factor inhibitors (TNFi) and/or non-biologic disease-modifying antirheumatic drugs (DMARDs).Patients and methods: Adult COPD patients with ≥1 diagnosis for rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) before or within 6 months following the index COPD diagnosis were identified from the Truven Health MarketScan® databases. Patients were required to have a second claim for RA, PsO, PsA, AS, or DMARD use (biologic or non-biologic) prior to or up to 6 months following the index date. Incidence of COPD-related hospitalizations and emergency room (ER) visits was evaluated in relation to treatment with TNFi and/or DMARDs and other potential risk factors.Results: The study cohort included 40,687 patients (untreated, 37.7%; non-biologic DMARD, 35.4%; TNFi + non-biologic DMARD, 18%; TNFi, 8.8%). The proportion of patients with a COPD-related hospitalization and the incidence of COPD-related hospitalization (per 100 person-years) were lowest in the TNFi cohort (8.6%; 3.54, 95% confidence interval [CI]: 3.16–3.95) and the TNFi + non-biologic DMARD cohort (8.4%; 2.85, 95% CI: 2.63–3.08). In multivariate models, treatment with TNFi + non-biologic DMARD reduced the risk of COPD-related hospitalization or ER visits by 32% relative to non-biologic DMARDs (hazard ratio: 0.68; 95% CI: 0.61–0.75).Conclusion: In real-world settings, TNFi monotherapy confers similar risk for COPD-related hospitalization or ER visits as a non-biologic DMARD. Decreased risk was found among those treated with both TNFi and a non-biologic DMARD. Keywords: COPD, TNF inhibitor, exacerbation, incidence, biologic DMARD

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.

Background Optimal treatment regimens and measuring outcomes in psoriatic arthritis (PsA) remain key areas of research. Objectives To examine methotrexate (MTX) and etanercept (ETN) as monotherapy or in combination in a randomized trial and assess the relative performance of PsA-specific composite measures using trial efficacy data. Methods Patients with active PsA naive to biologic drugs (no prior MTX for PsA) were randomized to 3 groups for 48 weeks: ETN 50mg+MTX 20mg weekly (Combo; N=283); ETN 50mg+placebo weekly (ETN-mono; N=284); or MTX 20mg+placebo weekly (MTX-mono; N=284). At week 24, the American College of Rheumatology (ACR)20 and Minimal Disease Activity (MDA) responses were the primary and key secondary endpoints, respectively. Other PsA-specific composite measures used for disease activity included the Psoriatic Arthritis Disease Activity Score (PASDAS) and Disease Activity Index for Psoriatic Arthritis (DAPSA). Results Baseline characteristics were well balanced in the 3 arms. Mean (SD) age was 48.4 (13.1) years and mean/median PsA duration 3.2/0.6 years. ACR20 and MDA responses at week 24 were significantly greater with ETN-mono vs MTX-mono and Combo vs MTX-mono; ETN-mono and Combo had similar results (Table). PASDAS also showed differences between each ETN-containing arm vs MTX-mono and no difference for ETN-mono vs Combo, whereas study arm differences were not seen with DAPSA. PASDAS had a greater effect size and standardized response than DAPSA. Conclusion In this large randomized, controlled PsA trial, ETN-mono or Combo had greater efficacy than MTX-mono. Combining ETN and MTX did not improve ETN efficacy. Compared with the joint-focused DAPSA, PASDAS captured a wider range of PsA manifestations and performed better in this trial. Disclosure of Interests: Philip J Mease Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, SUN and UCB, Consultant for: AbbVie, Amgen, BMS, Galapagos, Gilead Sciences, Inc., Janssen, Lilly, Novartis, Pfizer, SUN and UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Novartis, Pfizer and UCB, Dafna D Gladman Grant/research support from: AbbVie, Amgen, Celgene, Lilly, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, David Collier Shareholder of: Amgen Inc., Employee of: Amgen Inc., Christopher T. Ritchlin Grant/research support from: AbbVie, Amgen, UCB Pharma, Consultant for: AbbVie, Amgen, Lilly, Novartis, Pfizer, UCB Pharma, Philip Helliwell Grant/research support from: Paid to charity: from AbbVie, Janssen and Novartis, Consultant for: Paid to charity: from AbbVie, Amgen, Pfizer, and UCB and Celgene. Paid to self: from Celgene and Galapagos, Laura C Coates Grant/research support from: AbbVie, Celgene, Lilly, Novartis and Pfizer, Consultant for: AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead Sciences Inc., Janssen, Lilly, Novartis, Pfizer, Prothena Corp and UCB, Vibeke Strand Consultant for: AbbVie, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, Celltrion, CORRONA, Crescendo, EMD Serono, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kezar, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Servier, UCB., Lyrica Liu Shareholder of: Amgen Inc., Employee of: Amgen Inc., Greg Kricorian Shareholder of: Amgen Inc., Employee of: Amgen Inc., James Chung Shareholder of: Amgen Inc., Employee of: Amgen Inc.

Response to etanercept therapy in patients who have failed apremilast therapy has not been well characterized.In this multicenter, open-label, single-arm, phase 4, estimation study, subjects with moderate to severe plaque psoriasis received etanercept 50 mg SC twice weekly for 12 weeks, followed by etanercept 50 mg SC once weekly for an additional 12 weeks. Subjects had BSA greater than equal to 10%, PASI greater than equal to 10, and sPGA greater than equal to 3 at screening and baseline; and had failed apremilast-because of either failure to achieve or loss of adequate clinical response, or intolerability to apremilast in the opinion of the investigator. Primary endpoint was PASI 75 at week 12. Secondary endpoints included PASI 75 at week 24, PASI 90 at weeks 12 and 24, and patient-reported outcomes: Psoriasis Symptom Inventory (PSI) score (total and individual items) at baseline and weeks 12 and 24, and over time; DLQI responder analysis (5-point improvement in DLQI from baseline or score of 0) at weeks 12 and 24; and patient assessment of treatment satisfaction at baseline and weeks 12 and 24.Among 80 patients, PASI 75 at weeks 12 and 24 was 41.6% (95% CI, 30.4%-53.4%) and 45.5% (34.1%-57.1%), respectively; PASI 90 was 13.0% (6.4%-22.6%) and 22.1% (13.4%-33.0%), respectively. Mean total PSI score (LOCF) improved from 16.6 (95% CI, 15.1-18.0) at baseline to 8.8 (7.3-10.2) and 9.6 (7.9-11.4) at weeks 12 and 24, respectively; improvements in item PSI scores were similar. The percentage of DLQI responders was 66.2% (95% CI, 54.3%-76.8%) and 57.3% (45.4%-68.7%) at weeks 12 and 24, respectively. The percentage of subjects who were satisfied/very satisfied with their psoriasis treatment improved from 5.0% at baseline to 60.8% and 53.3% at weeks 12 and 24, respectively. During the 24-week study, 23.8% and 2.5% of subjects reported an adverse event and serious adverse event, respectively; there were no new safety signals in this study.In patients who have failed apremilast, etanercept may represent an effective therapeutic option.ClinicalTrials.gov: NCT02749370 J Drugs Dermatol. 2018;17(10):1078-1082.

Objective To assess the safety and immunologic impact of inhibiting interferon-γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE). Methods Twenty-six patients with mild-to-moderate, stable SLE were administered placebo or a single dose of AMG 811, ranging from 2 mg to 180 mg subcutaneously or 60 mg intravenously. Results Similar to results previously reported following inhibition of type I IFNs, treatment of SLE patients with AMG 811 led to a dose-dependent modulation of the expression of genes associated with IFN signaling, as assessed by microarray analysis of the whole blood. The list of impacted genes overlapped with that identified by stimulating human whole blood with IFNγ and with those gene sets reported in the literature to be differentially expressed in SLE patients. Serum levels of IFNγ-induced chemokines, including IFNγ-inducible protein 10 (IP-10), were found to be elevated at baseline in SLE patients as compared to healthy volunteers. In contrast to previously reported results from studies using type I IFN–blocking agents, treatment with AMG 811 led to dose-related reductions in the serum levels of CXCL10 (IP-10). Conclusion The scope and nature of the biomarkers impacted by AMG 811 support targeting of IFNγ as a therapeutic strategy for SLE.

The objective of this study is to characterize stability and clinical features of patients with rheumatoid arthritis (RA) in sustained remission. Combination therapy with methotrexate and tumor necrosis factor inhibitors (TNFi) has increased remission rates in RA but optimal regimens to maintain remission are unknown. We describe Study of Etanercept And Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis (SEAM-RA) and data from a run-in period of longitudinal observation. Patients in Simplified Disease Activity Index (SDAI) remission (score ≤ 3.3) receiving etanercept and methotrexate were screened and had to maintain remission over 3 run-in visits/24 weeks before randomization to combination therapy or withdrawal of etanercept or methotrexate. Baseline characteristics were examined for predictive factors for maintaining remission. As of November 2016, 141 patients have enrolled; of these, 64 have been randomized, 34 were ineligible after run-in, and 43 are in run-in period; 70% have completed run-in. Enrolled and randomized patients, respectively, had mean (standard deviation [SD]) disease duration 11.0 (8.6) and 12.6 (9.7) years; mean (SD) duration of etanercept use 4.2 (3.8) and 4.9 (4.2) years; mean (SD) methotrexate dose 15.9 (4.8) and 15.5 (4.9) mg/week; and mean (SD) SDAI scores 1.5 (0.9) and 1.4 (0.8). At enrollment, 73% and 63% were in Boolean remission based on 28 joints and 66/68 joints, respectively. No enrollment characteristic predicted successful completion of run-in. Two-thirds of patients considered to be in remission at enrollment sustained remission through 24 weeks. Baseline characteristics of enrolled patients and those who completed run-in were comparable. Electronic supplementary material The online version of this article (10.1007/s10067-017-3923-z) contains supplementary material, which is available to authorized users.

Background Blockade of inducible costimulatory ligand (ICOSL) might be a promising approach for autoimmune diseases such as systemic lupus erythematosus (SLE). We evaluated AMG 557, an anti-ICOSL monoclonal antibody, in an exploratory phase 1b study of SLE subjects with inflammatory arthritis, by withdrawing background therapies to improve interpretability of a small study. Objectives To investigate potential efficacy, safety, and tolerability of AMG 557 in subjects with lupus arthritis. Methods This double-blind, randomized, placebo-controlled trial enrolled subjects with SLE and active lupus arthritis (≥4 tender and 4 swollen joints) and Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] score ≥6 despite stable background immunosuppressants. Upon enrollment, investigators were permitted to use up to 20 mg/day of prednisone, which was tapered by day 85 to 7.5 mg/day or 50% of baseline, whichever was lower. Subjects received AMG 557 210 mg or placebo once weekly for 3 weeks followed by 10 additional doses every other week until day 155. At day 29, background immunosuppressants were withdrawn. The primary clinical endpoint was a composite Lupus Arthritis Responder Index at day 169; response was defined as achieving: (1) 50% decrease in combined tender and swollen joint counts, and (2) ≥1 letter improvement in the musculoskeletal subsystem of the British Isles Lupus Assessment Group (BILAG) index and (3) prespecified immunosuppressant medication withdrawal and/or prednisone taper. Safety was a co-primary endpoint. Exploratory endpoints included safety, 4-point reduction of SLEDAI, clinical indices (SLEDAI, BILAG), complement components, autoantibodies, and lymphocyte populations. Results Twenty subjects (19 females) were randomized (10 AMG 557, 10 placebo) at 8 sites in North America, Asia, and Europe. The primary endpoint was met by 3/10 subjects receiving AMG 557 and 1/10 subjects receiving placebo ( P =ns). A 4-point decrease in SLEDAI score was achieved by 7/10 subjects on AMG 557 and 2/10 subjects on placebo. At day 169, subjects receiving AMG 557 had decreases from baseline in mean global BILAG and SLEDAI scores of 36% and 48% respectively, compared to 25% and 11% in subjects receiving placebo. Lupus-associated biomarkers, including serum complement indices (C3, C4, and CH50), and autoantibodies, including anti-dsDNA, demonstrated trends towards improvement relative to placebo. Treatment-emergent adverse events (AEs) were similar between placebo and AMG 557 arms; most commonly headache and upper respiratory tract infection. Conclusions Results from this exploratory placebo-controlled trial in lupus arthritis suggest potential clinical benefit of ICOSL blockade by AMG 557. These data support further clinical trials intervening in this costimulatory pathway in SLE and other autoimmune diseases. Disclosure of Interest L. Cheng Shareholder of: Amgen Inc., Employee of: Amgen Inc., Z. Amoura Consultant for: GlaxoSmithKline, AstaZeneca, BristolMyerSquibb, Amgen Inc., B. Cheah Grant/research support from: Merck, F. Hiepe Grant/research support from: Sanofi, Amgen Inc., GlaxoSmithKline, AstaZeneca, Ablynx, Consultant for: Baxalta, AstaZeneca, BristolMyerSquibb, GlaxoSmithKline, Novartix, Miltenyi, Neovacs, Hexal, Neovi, Speakers bureau: Pfizer Inc., Roche, UCB, B. Sullivan Shareholder of: Amgen Inc., Employee of: Amgen Inc., L. Zhou Shareholder of: Amgen Inc., Employee of: Amgen Inc., G. Arnold Shareholder of: Amgen Inc., Employee of: Amgen Inc., W. Tsuji Shareholder of: Amgen Inc., JohnsonJ Partner in the Cascadia Drug Development Group, J. Merrill Consultant for: EMD Serono, BristolMyerSquibb, Human Genome Sciences, UCB, AstraZeneca, Celgene, J. Chung Shareholder of: Amgen Inc., Employee of: Amgen Inc.

SummaryBackground Some patients with plaque psoriasis experience secondary failure of tumour necrosis factor inhibitor therapy. Objectives To evaluate efficacy, safety and patient-reported outcomes (PROs) with etanercept in patients with secondary adalimumab failure. Methods This phase IV open-label single-arm estimation study (NCT01543204) enrolled patients on adalimumab who had achieved static Physician's Global Assessment (sPGA) score 0/1 (clear/almost clear). Patients subsequently lost response, defined as sPGA ≥ 3 or loss of 50% improvement in Psoriasis Area and Severity Index (PASI 50). At baseline, patients had involved body surface area ≥ 10%, sPGA ≥ 3 and PASI ≥ 10. Antiadalimumab antibodies (ADAs) were measured at screening. Patients received etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly. The primary end point was sPGA 0/1 at week 12 (intention-to-treat analysis; no hypothesis tested). Additional outcomes included rates of sPGA 0/1, PASI responses, safety, PROs of itch, pain and flaking, Dermatology Life Quality Index, treatment satisfaction and Work Productivity and Activity Impairment questionnaire. Results Sixty-four patients enrolled; 67% had ADAs. sPGA 0/1 rates at week 12 were 39·7% [95% confidence interval (CI) 27·6–52·8; primary end point] and 45% (95% CI 29·3–61·5) for patients positive for ADAs and 35% (95% CI 15·4–59·2) for patients negative for ADAs. PASI 75 response rates at week 12 were 47·5% (95% CI 31·5–63·9) for patients who were positive for ADAs and 50% (95% CI 27·2–72·8) for patients negative for ADAs. No new safety signals were observed. PROs of itch, pain and flaking consistently improved at week 12 and were maintained through week 24. Conclusions Patients with psoriasis who experienced secondary failure of adalimumab achieved satisfactory response to etanercept regardless of ADA status.

ObjectiveTo comprehensively assess evidence on the measurement properties of the minimal disease activity (MDA) criteria, a composite measure of the state of disease activity in psoriatic arthritis (PsA).MethodsA targeted literature review was conducted to identify studies that informed the validity and/or ability of the MDA to detect change among patients known to have experienced a change in clinical status. The search was conducted using MEDLINE and Embase databases (published as of October 2017). Pertinent articles provided by investigators and identified from select conference proceedings were also evaluated.ResultsA total of 20 publications met the inclusion criteria. The MDA criteria were consistently associated with other indicators of disease activity/severity. The ability of the MDA criteria to detect change was supported in randomised controlled trials (n=10), with a greater percentage of patients randomised to active treatments achieving MDA relative to patients in comparator arms. Long-term observational studies (n=2) provided additional support for the ability of the MDA to detect within-subject change in the real-world settings.ConclusionEvidence supports the MDA as a valid measure of disease activity in PsA that can detect between-group and within-subject change. The MDA is a comprehensive measure and clinically meaningful endpoint to assess the impact of interventions on PsA disease activity.

The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics.

OBJECTIVE: Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi-methotrexate versus triple therapy in patients with RA.METHODS: A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi-methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi-methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models.RESULTS: We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi-methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi-methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate.CONCLUSIONS: In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi-methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi-methotrexate, no clear differences were observed. The odds of infection were greater with TNFi-methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.

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.

Objective Interferon-γ (IFNγ) is implicated in the pathogenesis of discoid lupus erythematosus (DLE). This study sought to evaluate a single dose of AMG 811, an anti-IFNγ antibody, in patients with DLE. Methods The study was designed as a phase I randomized, double-blind, placebo-controlled crossover study of the pharmacodynamics, safety, and clinical efficacy of AMG 811 in patients with DLE. Patients received a single subcutaneous dose of AMG 811 (180 mg) or placebo. The patients in sequence 1 received AMG 811 followed by placebo, while those in sequence 2 received placebo followed by AMG 811. Pharmacodynamic end points included global transcriptional analyses of lesional and nonlesional skin, IFNγ blockade signature (IGBS) transcriptional scores in the skin and blood, keratinocyte IFNγ RNA scores, and serum levels of CXCL10 protein. Additional end points were efficacy outcome measures, including the Cutaneous Lupus Erythematosus Disease Area and Severity Index, and safety outcome measures. Results Sixteen patients with DLE were enrolled in the study (9 in sequence 1 and 7 in sequence 2). AMG 811 treatment reduced the IGBS score (which was elevated in DLE patients at baseline) in both the blood and lesional skin. The keratinocyte IFNγ RNA score was not affected by administration of AMG 811. Serum CXCL10 protein levels (which were elevated in the blood of DLE patients) were reduced with AMG 811 treatment. The AMG 811 treatment was well tolerated but did not lead to statistically significant improvements in any of the efficacy outcome measures. Conclusion AMG 811 treatment led to changes in IFNγ-associated biomarkers and was well tolerated, but no significant clinical benefit was observed in patients with DLE.

Objectives o evaluate the efficacy of etanercept and methotrexate as monotherapies and as combination therapy in subjects with active psoriatic arthritis (PsA). Methods he Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA) is an ongoing, global, doubleblind, 48-week, randomised, controlled study. Subjects are randomised (1:1:1) to etanercept monotherapy, methotrexate monotherapy or etanercept-methotrexate combination therapy. Endpoints include rates of ACR20 response and Minimal Disease Activity, measures to characterise extra-articular manifestations (dactylitis, enthesitis, nail disease) and safety. Conclusion SEAM-PsA will characterise the effects of etanercept with and without background methotrexate and methotrexate alone on PsA manifestations, and provide information of practical importance to clinicians on the optimal treatment of PsA.

The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.

This study evaluated the efficacy and safety of adding etanercept to disease-modifying antirheumatic drugs (DMARDs) in patients with moderately active rheumatoid arthritis (RA). This randomized, double-blind, placebo-controlled study (ClinicalTrials.gov #NCT01313208) enrolled RA patients with Disease Activity Score using 28 joints with C-reactive protein (DAS28-CRP) >3.2 and ≤5.1 (moderate disease) despite stable DMARD therapy. Patients were randomized to etanercept 50 mg or placebo weekly for 12 weeks; all patients then received etanercept 50 mg weekly through week 24. Primary endpoint was low disease activity (LDA) at week 12; secondary endpoints included DAS28-CRP remission at week 12; Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) LDA; American College of Rheumatology (ACR) responses; change in Health Assessment Questionnaire Disability Index (HAQ-DI), and safety. For 210 patients with moderate disease at screening, (104 placebo; 106 etanercept), only 58% still had moderate disease at baseline. At week 12, 33% on etanercept and 21% on placebo achieved LDA (P = 0.055); remission was achieved in 19% and 12%, respectively (P = 0.14). At week 12, ACR20, ACR50, and ACR70 responses were observed in 29%, 13%, and 1% respectively, in patients on placebo, and 41%, 21%, and 6% of patients on etanercept. Mean (SD) change from baseline in HAQ-DI score was −0.20 (0.43) for placebo patients and −0.39 (0.54) for etanercept patients at week 12. No new safety signals were observed. LDA was achieved by more patients on etanercept than placebo in patients with moderate disease at screening, but the difference was not statistically significant at week 12.

Transitional B cells mark the crucial link between bone-marrow (BM) immature and peripheral mature B cells. Examination reveals unexpected heterogeneity, consisting of contiguous subsets with phenotypic and functional differences. Data point to the late transitional B-cell stage as a crucial juncture at which developing B cells gain access to splenic follicles, become responsive to T-cell help and lose sensitivity to negative selection, characterizing the immature B-cell response to B-cell antigen receptor (BCR) signaling in vitro and in vivo. The biological and molecular processes directing maturation through this stage are becoming clearer through biochemical studies and murine models deficient in various components of the BCR signaling pathway.

Our laboratory is interested in a variety of issues related to lymphocyte development. More specifically, we have focused on the processes that regulate the decision to commit to the B lymphocyte (B cell) lineage, then the subsequent signals that are involved in maintaining this commitment to the B cell lineage. These signals result in the positive selection of those B cells that properly execute the complex genetic changes associated with B cell development, then trigger the elimination of B cells that are responsive to self-antigens and, therefore, possess the potential to mediate autoimmune disease. Our general experimental approach has been to address these issues from the perspective of signal transduction. Our goal is to define the biochemical and genetic processes that are integrated in order to accomplish these selection processes. To do so, we employ in vivo animal models as well as more defined in vitro studies, using both primary and transformed cell lines. For the past several years, we have been primarily interested in the precise mechanisms by which the B cell antigen receptor (BCR), and intermediate forms of this receptor, regulate these complex developmental processes. We have used the ongoing studies described below as two representative examples of how we are approaching these issues and some of the insights that we have made. To place both of these studies in context, we will begin with a brief introduction into B cell development.

Objective To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN). Methods In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement). Results Fifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed. Conclusion AMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects. Trial registration number NCT00818948; results.

Objective To assess the incremental cost-effectiveness of 3 Pneumocystis carinii pneumonia (PCP) prophylaxis strategies in patients with Wegener's granulomatosis (WG) receiving immunosuppressive therapies: 1) no prophylaxis; 2) trimethoprim/sulfamethoxazole (TMP/SMX) 160 mg/800 mg 3 times a week, which is discontinued if patients experience an adverse drug reaction (ADR); and 3) TMP/SMX 160 mg/800 mg 3 times a week, which is replaced by monthly aerosolized pentamidine (300 mg) if patients experience an ADR. Methods A Markov state-transition model was developed to follow a hypothetical cohort of WG patients over their lifetimes starting from the time of initial exposure to the immunosuppressive therapy. The effect of PCP prophylaxis on life expectancy, quality-adjusted life expectancy, average discounted lifetime cost (ADLC), and incremental cost-effectiveness was estimated based on data obtained from a literature review. Direct medical costs were examined from a societal perspective, and costs and benefits were discounted at 3% annually. Results No prophylaxis resulted in a life expectancy of 13.36 quality-adjusted life years (QALY) at an ADLC of $4,538. In comparison, prophylaxis with TMP/SMX alone increased the QALY to 13.54 and was cost saving, with an ADLC of $3,304. The addition of pentamidine in patients who had an ADR to TMP/SMX resulted in 13.61 QALY, with an ADLC of $7,428. Compared with TMP/SMX alone, TMP/SMX followed by pentamidine increased the QALY by 0.07 at an incremental cost of $58,037 per QALY. Both TMP/SMX alone and TMP/SMX followed by pentamidine prophylaxis strategies dominated the no prophylaxis strategy until the incidence of PCP fell below 0.2% and 2.25%, respectively. Institution of pentamidine therapy for patients with a TMP/SMX ADR increased quality-adjusted life expectancy compared with that with TMP/SMX alone until the incidence of PCP rose above 7.5%. Conclusion Prophylaxis using TMP/SMX alone increased life expectancy and reduced cost for patients with WG receiving immunosuppressive therapy. Replacing TMP/SMX with monthly aerosolized pentamidine in cases of ADR further increased life expectancy, although at an increased cost.

To discuss the strategies for preclinical and early clinical characterization of targeted antifibrotic therapies in order to optimize the probability of positive results in later stage clinical trials.There is a high unmet clinical need for effective antifibrotic therapies in systemic sclerosis (SSc), and in parallel a rapid development in the identification of potential molecular targets in preclinical research. Herein, we discuss the strategies for the improvement of preclinical and early clinical trials. These strategies include identification and characterization of molecular targets for therapy in vitro, selection of relevant parameters in translational animal models, confirmation of target activation in human SSc, analysis of successful target coverage after drug exposure in human SSc, and conduct of biomarker-driven proof-of-concept studies as a bridge between animal studies and Phase IIB/III studies with clinical endpoints.These strategies could increase the possibility to develop successful drugs against the fibrotic manifestations of SSc.

Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (TFH cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of TFH cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F1 mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in TFH cells and GC B cells as well as an overall decrease in the frequency of ICOS+ T cells. Coculture experiments of Ag-primed B cells with CXCR5+ or CXCR5− T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the TFH cell pool is an important mechanism by which ICOS regulates Ab production.

Objective: Characterization of peripheral leukocytes is an important aspect of monitoring the effect of immunotherapeutic interventions in systemic lupus erythematosus (SLE). We analyzed cell surface markers commonly used to assess patients with SLE, focusing on the effect of holding blood prior to processing/analysis and the relative reliability of the measurements that were conducted. Methods: Healthy volunteers (HV; n = 20) and patients with SLE (n = 42) were studied. Whole blood was collected for flow cytometric analysis on days 1, 8, 15, 105, 195, 285, and 375 and held overnight for analysis. A subset of samples was additionally analyzed on the day of collection. Results: Variability arising from overnight storage of whole blood was found to be within 20% for most lymphocyte subsets. There was greater between rather than within subject variability over a 1-year period. As anticipated, the data showed higher CD38 and lower CD19 densities on B cells from patients with SLE compared to HV. Although a higher percentage of cells with markers of plasmablasts/cells were observed in the blood of patients with SLE relative to HV, these measurements were found to be among the least reliable (i.e., most variable). Conclusions: This study provides technical perspectives for those conducting immunophenotypic analyses of B-cells in patients with SLE. We envision that our data, which addresses sample stability issues and presents a method to describe the relative reliability of one measure over another, holds value for clinical assessments of B-cells in SLE and the evaluation of investigational agents designed to modify the B-cell compartment. © 2009 Clinical Cytometry Society

Background Interferon-gamma (IFN-g) is a pro-inflammatory cytokine that modulates the function of several important immune populations. Evidence from human and animal models suggests that increased levels of Type I and/or Type II IFN are associated with SLE. Objectives This study assessed the safety, tolerability, PK and pharmacodynamic (PD) data from AMG 811, an anti-IFNg mAb, in subjects with active class III or IV LN. Methods Subjects were enrolled if they had new onset or reactivation of biopsy-proven (within 18 months) class III or IV LN, UP/Cr >1 or 24 hr urine protein >1 g after at least 12 wks of treatment with MMF or AZA. Superimposed membranous changes were allowed. Subjects with rapidly progressive GN or significant chronicity were excluded. Subjects could receive oral prednisone at doses up to 20 mg/day. Subjects were randomized to placebo or ascending doses of AMG 811 (20, 60 or 120 mg given SC q4 wks for three doses at 3:1 allocation) in addition to MMF or AZA. The primary endpoints were safety, tolerability, and anti-drug antibodies. Serum AMG 811 concentrations, anti-AMG 811 antibodies and PD biomarkers (blood RNA and serum) were also assessed. Disease related assessments included reduction from baseline in proteinuria (24 hr urine and spot UP/Cr), SLEDAI scores and changes in SLE-related biomarkers. Results 28 subjects were enrolled: 7 in the PBO group and 21 in the AMG 811 treatment groups. The proportion of subjects reporting treatment emergent AEs, including serious AEs, was similar between PBO and AMG 811 groups although a numerically higher proportion of subjects treated with AMG 811 had infectious events. AMG 811 displayed linear PK with half-life of 11-21 days. Exposures after doses of 20 & 60 mg in LN subjects were similar to exposures in non-renal SLE subjects. Antibodies to AMG 811 were not observed at any time. Baseline serum CXCL10 (IP-10) levels and IFNgamma-modulated mRNAs were higher in LN compared to non-renal SLE; both populations had elevated levels compared to healthy controls. AMG 811 (60 & 120 mg cohorts) led to a reduction in these biomarkers, albeit incomplete and transient, suggesting that AMG 811 may have had reduced target coverage in LN relative to non-renal SLE, where levels were reduced into the healthy range. Although numerous subjects demonstrated improvement in proteinuria, no consistent differences between AMG 811 treatment cohorts and PBO were discernable at week 12 in renal outcome or SLE-related serum biomarkers. Conclusions AMG 811 demonstrated a favorable PK and immunogenicity profile in active LN subjects, and the overall safety profile was acceptable in this small study. Inhibition of pharmacodynamic biomarkers with doses up to 120 mg of AMG 811 appeared incomplete in LN subjects. There were no discernible effects of AMG 811 on clinical or SLE-related serologic outcome measures over the treatment period although interpretation is challenging given the small sample size. Disclosure of Interest D. Martin Employee of: Amgen, Z. Amoura: None declared, J. Romero-Diaz: None declared, Y. Chong: None declared, J. Sanchez-Guerrero: None declared, T. Chan: None declared, G. Arnold Employee of: Amgen, M. Damore Employee of: Amgen, W. Sohn Employee of: Amgen, N. Chirmule Employee of: Amgen, K. Chiu Employee of: Amgen, C. Wang Employee of: Amgen, M. Boedigheimer Employee of: Amgen, B. Sullivan Employee of: Amgen, A. Welcher Employee of: Amgen, B. Kotzin Employee of: Amgen, J. Chung Employee of: Amgen

B cells leave the bone marrow as transitional B cells. Transitional B cells represent a target of negative selection and peripheral tolerance, both of which are abrogated in vitro by mediators of T cell help. In vitro, transitional and mature B cells differ in their responses to B cell receptor ligation. Whereas mature B cells up-regulate the T cell costimulatory molecule CD86 (B7.2) and are activated, transitional B cells do not and undergo apoptosis. The ability of transitional B cells to process and present Ag to CD4 T cells and to elicit protective signals in the absence of CD86 up-regulation was investigated. We report that transitional B cells can process and present Ag as peptide:MHC class II complexes. However, their ability to activate T cells and elicit help signals from CD4-expressing Th cells was compromised compared with mature B cells, unless exogenous T cell costimulation was provided. A stringent requirement for CD28 costimulation was not evident in interactions between transitional B cells and preactivated CD4-expressing T cells, indicating that T cells involved in vivo in an ongoing immune response might rescue Ag-specific transitional B cells from negative selection. These data suggest that during an immune response, immature B cells may be able to sustain the responses of preactivated CD4+ T cells, while being unable to initiate activation of naive T cells. Furthermore, the ability of preactivated, but not naive T cells to provide survival signals to B cell receptor-engaged transitional immature B cells argues that these B cells may be directed toward activation rather than negative selection when encountering Ag in the context of a pre-existing immune response.

Objective A vaccine for Lyme disease was approved in 1998 for use in the US. Given the high cost of the vaccine, the low risk of Lyme disease in many areas, and the largely curable nature of the disease, the cost-effectiveness of the vaccine in various risk groups is uncertain. This study was undertaken to examine the cost-effectiveness of the Lyme disease vaccine and the factors that influence its cost-effectiveness. Methods We constructed a Markov decision-analysis model to evaluate the clinical effectiveness and cost-effectiveness of the Lyme disease vaccine in populations at various levels of risk for the disease. The probabilities of clinical events and costs were estimated from reports in the literature. Sensitivity analyses assessed the impact of potential variations of parameters on model results. Results At the average national incidence of Lyme disease (0.0067%), the incremental cost-effectiveness of vaccination was ∼$1,600,000 per case averted when a yearly booster was given for 10 years after the standard initial vaccination regimen of 3 inoculations at 0, 1, and 12 months. For populations with an annual Lyme disease incidence of 1% (the incidence in several well-defined geographical areas of the US), the incremental cost-effectiveness was ∼$9,900 per case averted. Disease incidence had to exceed 10% before vaccination with yearly boosters became both more effective and more cost saving than no vaccination. Conclusion The Lyme disease vaccine is cost-effective only for individuals who live in areas where Lyme disease is endemic and who are frequently exposed to ticks.

Transitional immature B cells undergo apoptosis and fail to proliferate in response to BCR cross-linking, thus representing a target for negative selection of potentially autoreactive B cells in vivo. In agreement with recent reports, transitional B cells were divided into developmentally contiguous subsets based on their surface expression of CD23. When transferred, CD23(+) transitional B cells readily localized to the splenic follicles and the outer PALS. Compared with CD23(-) transitional B cells, CD23(+) transitional B cells proliferated more vigorously and were rescued from BCR-induced apoptosis to a greater degree, by T cell help signals. However, both CD23(-) and CD23(+) transitional B cells failed to up-regulate CD86 (B7-2) in response to BCR ligation. These findings demonstrate that phenotypically defined subsets within the transitional B cell population are functionally distinct. Specifically, responsiveness to T cell help is a late acquisition corresponding to the stage when the B cells gain access to peripheral compartments enriched in antigen and activated T cells. The failure of transitional B cells to up-regulate CD86 to BCR-mediated stimulation suggests a unique interaction between transitional B cells and T cells with implications for tolerance in the T cell compartment.

Background Patients (pts) with moderately active RA represent a medically important subset of RA pts. Numerous clinical trials indicate that a substantial number of pts with moderate RA can achieve recommended treatment targets. Objectives To evaluate whether adding ETN to standard-of-care DMARD therapy in pts with moderate RA is superior in inducing LDA (Disease Activity Score using 28 joints with C-reactive protein [DAS28-CRP] Methods This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with DAS28-CRP >3.2 and ≤5.1 despite being on stable DMARD therapy at screening. After a screening window of up to 31 days, pts were randomized to receive ETN 50mg or PBO weekly for 12 weeks followed by ETN 50mg weekly for an additional 12 weeks. Endpoints included rates of LDA at week 12 (primary endpoint), remission (DAS28-CRP Results For the primary analysis set of 210 enrolled pts (104 PBO; 106 ETN), baseline mean (standard deviation [SD]) DAS28-CRP was 4.88 (0.81) and 4.88 (0.69) for PBO and ETN pts, respectively, and mean (SD) HAQ scores were 1.20 (0.68) and 1.28 (0.64). At week 12, more pts randomized to ETN than PBO were in DAS28-CRP LDA (33% vs 21%; P =0.055) and DAS28-CRP remission (19% vs 12%; P =0.14) but the results were not statistically significant. Improvement in the PBO treatment group and lack of continued improvement in the ETN treatment group was observed between weeks 8 and 12 as rates of DAS28-CRP LDA were statistically significantly different at week 8 (ETN 34%, PBO 16%; P =0.003). Of note, of the 210 pts in the primary analysis set, 194 (92%) pts had moderate RA at screening but only 122 (58%) pts had moderate RA at baseline. For the subset of pts with moderate disease at baseline, 18% of PBO pts and 42% of ETN pts achieved LDA at week 12. Rates of ACR20, ACR50, and ACR70 responses improved from week 2 through week 24 in both treatment groups. At week 12, ACR20, ACR50, and ACR70 responses were observed in 30%, 13%, and 1% of PBO pts, respectively, and 42%, 22%, and 6% of ETN pts. Mean change (SD) in HAQ-DI score was -0.20 (0.43) for PBO pts and -0.39 (0.54) for ETN pts at week 12 ( P =0.024). No new or unexpected safety findings were observed. Conclusions ETN led to the induction of LDA in a greater proportion of pts compared with PBO in pts with moderate disease, although the difference was not statistically significant at week 12 in the primary analysis set of pts with moderate disease at screening. A post hoc analysis of the 122/210 pts who maintained moderate disease at baseline showed consistent evidence of efficacy across a broad set of outcome measures. Acknowledgements Study funded by Immunex, a wholly owned subsidiary of Amgen Inc. and by Wyeth, which was acquired by Pfizer in October 2009. Julie Wang (Amgen Inc.) and Julia R. Gage (on behalf of Amgen Inc.) provided medical writing support. Disclosure of Interest K. Hobbs Consultant for: Amgen Inc., J. Chung Shareholder of: Amgen Inc., Employee of: Amgen Inc., B. Bitman Shareholder of: Amgen Inc., Employee of: Amgen Inc., B. Wang Shareholder of: Amgen Inc., Employee of: Amgen Inc., J. Nussbaum Shareholder of: Amgen Inc., Employee of: Amgen Inc., D. Collier Shareholder of: Amgen Inc., Employee of: Amgen Inc. DOI 10.1136/annrheumdis-2014-eular.1253

Glycosphingolipid-enriched domains (GEDs) are believed to act as platforms for transduction of B cell Ag receptor (BCR)-induced signals from the cell surface. We sought to study whether differential sequestration of BCR into GEDs may contribute to the described intrinsic signaling differences between mature and immature B cells. In this study we found that mature B cells copolarize the BCR with GEDs following BCR aggregation, whereas transitional immature B cells do not. Although anti-BCR treatment leads to receptor aggregation by immature stage B cells, the aggregated complexes do not colocalize with GEDs. We found this difference to be independent of the isotype of the receptor, thereby associating this difference in BCR-GED colocalization to the developmental stage of the B cell. These findings suggest a structural basis for the developmentally regulated differences observed in Ag receptor-mediated signal transduction.

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