Efficacy and safety of secukinumab administration by autoinjector in patients with psoriatic arthritis: results from a randomized, placebo-controlled trial (FUTURE 3)

Background: The study aimed to assess 52-week efficacy and safety of secukinumab self-administration by autoinjector in patients with active psoriatic arthritis (PsA) in the FUTURE 3 study (ClinicalTrials.gov NCT01989468). Methods: Patients (≥ 18 years of age; N = 414) with active PsA were randomized 1:1:1 to subcutaneous (s.c.) secukinumab 300 mg, 150 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. Per clinical response, placebo-treated patients were re-randomized to s.c. secukinumab 300 or 150 mg at week 16 (nonresponders) or week 24 (responders) and stratified at randomization by prior anti-tumor necrosis factor (TNF) therapy (anti-TNF-naïve, 68.1%; intolerant/inadequate response (anti-TNF-IR), 31.9%). The primary endpoint was the proportion of patients achieving at least 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24. Autoinjector usability was evaluated by Self-Injection Assessment Questionnaire (SIAQ). Results: Overall, 92.1% (300 mg), 91.3% (150 mg), and 93.4% (placebo) of patients completed 24 weeks, and 84.9% (300 mg) and 79.7% (150 mg) completed 52 weeks. In the overall population (combined anti-TNF-naïve and anti-TNF-IR), ACR20 response rate at week 24 was significantly higher in secukinumab groups (300 mg, 48.2% (p < 0.0001); 150 mg, 42% (p < 0.0001); placebo, 16.1%) and was sustained through 52 weeks. SIAQ results showed that more than 93% of patients were satisfied/very satisfied with autoinjector usage. Secukinumab was well tolerated with no new or unexpected safety signals reported. Conclusions: Secukinumab provided sustained improvements in signs and symptoms in active PsA patients through 52 weeks. High acceptability of autoinjector was observed. The safety profile was consistent with that reported previously

Shooter localization and weapon classification with soldier-wearable networked sensors

The paper presents a wireless sensor network-based mobile countersniper system. A sensor node consists of a helmetmounted microphone array, a COTS MICAz mote for internode communication and a custom sensorboard that implements the acoustic detection and Time of Arrival (ToA) estimation algorithms on an FPGA. A 3-axis compass provides self orientation and Bluetooth is used for communication with the soldier’s PDA running the data fusion and the user interface. The heterogeneous sensor fusion algorithm can work with data from a single sensor or it can fuse ToA or Angle of Arrival (AoA) observations of muzzle blasts and ballistic shockwaves from multiple sensors. The system estimates the trajectory, the range, the caliber and the weapon type. The paper presents the system design and the results from an independent evaluation at the US Army Aberdeen Test Center. The system performance is characterized by 1-degree trajectory precision and over 95 % caliber estimation accuracy for all shots, and close to 100 % weapon estimation accuracy for 4 out of 6 guns tested

Direct observations of the kinetics of migrating T-cells suggest active retention by endothelial cells with continual bidirectional migration.

The kinetics and regulatory mechanisms of T-cell migration through endothelium have not been fully defined. In experimental filter-based assays in vitro, transmigration of lymphocytes takes hours, compared to minutes in vivo. We cultured endothelial cell (EC) monolayers on filters, solid substrates or collagen gels, and treated them with tumour necrosis factor-α (TNF), interferon-γ (IFN), or both, prior to analysis of lymphocyte migration in the presence or absence of flow. Peripheral blood lymphocytes (PBL), CD4+ cells or CD8+ cells, took many hours to migrate through EC-filter constructs for all cytokine treatments. However, direct microscopic observations of EC-filters which had been mounted in a flow chamber showed that PBL crossed the endothelial monolayer in minutes and were highly motile in the subendothelial space. Migration through EC was also observed on clear plastic, with or without flow. After brief settling without flow, PBL and isolated CD3+ or CD4+ cells all crossed EC in minutes, but the numbers of migrated cells varied little with time. Close observation revealed that lymphocytes continuously migrated back and forth across endothelium. Under flow, migration kinetics and the proportions migrating back and forth were little altered. On collagen gels, PBL again crossed EC in minutes and migrated back and forth, but showed little penetration of the gel over hours.In contrast, neutrophils migrated efficiently through EC and into gels. These observations suggest a novel model for lymphoid migration, in which endothelial cells support migration but retain lymphocytes (as opposed to neutrophils), and additional signal(s) are required for onward migration

Treatment recommendations for psoriatic arthritis

Objective: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Methods: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Results: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Conclusions: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available

Behavioral implications of shortlisting procedures

We consider two-stage “shortlisting procedures” in which the menu of alternatives is first pruned by some process or criterion and then a binary relation is maximized. Given a particular first-stage process, our main result supplies a necessary and sufficient condition for choice data to be consistent with a procedure in the designated class. This result applies to any class of procedures with a certain lattice structure, including the cases of “consideration filters,” “satisficing with salience effects,” and “rational shortlist methods.” The theory avoids background assumptions made for mathematical convenience; in this and other respects following Richter’s classical analysis of preference-maximizing choice in the absence of shortlisting

Synthesis of (+)-(R)-Tiruchanduramine

The absolute stereochemistry of the marine alkaloid (+)-(R)-tiruchanduramine was established via a convergent total synthesis in six steps and 15.5% overall yield from Fmoc-D-Dab(Boc)-OH

Interaction between integrin α9β1 and vascular cell adhesion molecule-1 (VCAM-1) inhibits neutrophil apoptosis

According to the prevailing paradigm, neutrophils are short-lived cells that undergo spontaneous apoptosis within 24 hours of their release from the bone marrow. However, neutrophil survival can be significantly prolonged within inflamed tissue by cytokines, inflammatory mediators, and hypoxia. During screening experiments aimed at identifying the effect of the adhesive microenvironment on neutrophil survival, we found that VCAM-1 (CD106) was able to delay both spontaneous and Fas-induced apoptosis. VCAM-1-mediated survival was as efficient as that induced by the cytokine IFN-β and provided an additive, increased delay in apoptosis when given in combination with IFN-β. VCAM-1 delivered its antiapoptotic effect through binding the integrin α9β1. The α9β 1 signaling pathway shares significant features with the IFN-β survival signaling pathway, requiring PI3 kinase, NF-κB activation, as well as de novo protein synthesis, but the kinetics of NF-κB activation by VCAM-1 were slower and more sustained compared with IFN-β. This study demonstrates a novel functional role for α9β1 in neutrophil biology and suggests that adhesive signaling pathways provide an important extrinsic checkpoint for the resolution of inflammatory responses in tissues

Analysis of the effects of stromal cells on the migration of lymphocytes into and through inflamed tissue using 3-D culture models

AbstractStromal cells may regulate the recruitment and behaviour of leukocytes during an inflammatory response, potentially through interaction with the endothelial cells (EC) and the leukocytes themselves. Here we describe new in vitro methodologies to characterise the effects of stromal cells on the migration of lymphocytes through endothelium and its underlying matrix. Three-dimensional tissue-like constructs were created in which EC were cultured above a stromal layer incorporating fibroblasts either as a monolayer on a porous filter or dispersed within a matrix of collagen type 1. A major advantage of these constructs is that they enable each step in leukocyte migration to be analysed in sequence (migration through EC and then stroma), as would occur in vivo. Migrated cells can also be retrieved from the constructs to identify which subsets traffic more effectively and how their functional responses evolve during migration. We found that culture of EC with dermal fibroblasts promoted lymphocyte transendothelial migration but not onward transit through matrix. A critical factor influencing the effect of fibroblasts on recruitment proved to be their proximity to the EC, with direct contact tending to disrupt migration. Comparison of the different approaches indicates that choice of an appropriate 3-D model enables the steps in lymphocyte entry into tissue to be studied in sequence, the regulatory mechanism to be dissected, and the effects of changes in stroma to be investigated

Secukinumab for psoriatic arthritis:comparative effectiveness versus licensed biologics/apremilast: a network meta-analysis

Aim: A network meta-analysis using randomized controlled trial data compared psoriatic arthritis (PsA) outcomes (American College of Rheumatology [ACR], Psoriasis Area Severity Index [PASI] and Psoriatic Arthritis Response Criteria [PsARC] response rates) at 12–16 weeks for secukinumab, adalimumab, apremilast, certolizumab, etanercept, golimumab, infliximab and ustekinumab. Patients & methods: Trials were identified by systematic review. Separate networks were developed for the full-study populations, biologic-naive patients and biologic-experienced patients. Results: In the full populations, secukinumab, adalimumab, golimumab and infliximab demonstrated the highest ACR response rates. Secukinumab and infliximab demonstrated the highest PASI response rates, and infliximab and etanercept demonstrated the highest PsARC response rates. Conclusion: In the full populations, secukinumab demonstrated good efficacy across all outcomes. All treatments for active PsA included in this comprehensive network meta-analysis demonstrated superiority to placebo

Book reviews

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43527/1/11116_2004_Article_BF00172656.pd