A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness

Objectives: This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-a (TNF-a), when used in the treatment of rheumatoid arthritis (RA) in adults. \ud \ud Data sources: Electronic databases were searched up to February 2005. \ud \ud Review methods: Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. \ud \ud Results: Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (≤3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. Etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage. Etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. Infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. Infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around £30,000 per quality-adjusted life-year (QALY) in early RA and £50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is £24,000 per QALY, substantially lower than for adalimumab (£30,000 per QALY) or infliximab (£38,000 per QALY). First line use as monotherapy generates ICERs around £50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. \ud \ud Conclusions: Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality

Observation of field-induced domain wall propagation in magnetic nanowires by magnetic transmission X-ray microscopy

Magnetic transmission X-ray microscopy (M-TXM) is used to image domain walls in magnetic ring structures formed by a 300 nm wide, 24 nm thick Ni{sub 81}Fe{sub 19} nanowire. Both transverse and vortex type domain walls are observed after application of different field sequences. Domain walls can be observed by comparing images obtained from opposite field sequences, or else domain wall propagation observed by comparing successive images in a particular field sequence. This demonstrates the potential use of M-TXM in developing and understanding planar magnetic nanowire behavior

Observation of field-induced domain wall propagation in magnetic nanowires by magnetic transmission X-ray microscopy

Abstract Magnetic transmission X-ray microscopy (M-TXM) is used to image domain walls in magneti

Convergent evolution of toxin resistance in animals

Convergence is the phenomenon whereby similar phenotypes evolve independently in different lineages. One example is resistance to toxins in animals. Toxins have evolved many times throughout the tree of life. They disrupt molecular and physiological pathways in target species, thereby incapacitating prey or deterring a predator. In response, molecular resistance has evolved in many species exposed to toxins to counteract their harmful effects. Here, we review current knowledge on the convergence of toxin resistance using examples from a wide range of toxin families. We explore the evolutionary processes and molecular adaptations driving toxin resistance. However, resistance adaptations may carry a fitness cost if they disrupt the normal physiology of the resistant animal. Therefore, there is a trade‐off between maintaining a functional molecular target and reducing toxin susceptibility. There are relatively few solutions that satisfy this trade‐off. As a result, we see a small set of molecular adaptations appearing repeatedly in diverse animal lineages, a phenomenon that is consistent with models of deterministic evolution. Convergence may also explain what has been called ‘autoresistance’. This is often thought to have evolved for self‐protection, but we argue instead that it may be a consequence of poisonous animals feeding on toxic prey. Toxin resistance provides a unique and compelling model system for studying the interplay between trophic interactions, selection pressures and the molecular mechanisms underlying evolutionary novelties

Manipulating ultracold atoms with a reconfigurable nanomagnetic system of domain walls

The divide between the realms of atomic-scale quantum particles and lithographically-defined nanostructures is rapidly being bridged. Hybrid quantum systems comprising ultracold gas-phase atoms and substrate-bound devices already offer exciting prospects for quantum sensors, quantum information and quantum control. Ideally, such devices should be scalable, versatile and support quantum interactions with long coherence times. Fulfilling these criteria is extremely challenging as it demands a stable and tractable interface between two disparate regimes. Here we demonstrate an architecture for atomic control based on domain walls (DWs) in planar magnetic nanowires that provides a tunable atomic interaction, manifested experimentally as the reflection of ultracold atoms from a nanowire array. We exploit the magnetic reconfigurability of the nanowires to quickly and remotely tune the interaction with high reliability. This proof-of-principle study shows the practicability of more elaborate atom chips based on magnetic nanowires being used to perform atom optics on the nanometre scale.Comment: 4 pages, 4 figure

Imaging of magnetic DW injection processed in patterened Ni80Fe20 structures

Magnetization reversal in patterned ferromagnetic nanowires usually occurs via domain wall (DW) nucleation and propagation from one end (or both ends) of the wire which can be significantly reduced by a large, magnetically soft pad on one of the wire ends. These 'nucleation pads' reverse at lower fields than an isolated nanowire and introduce a DW to the wire from the wire end attached to the pad. Once a critical 'injection' field is reached, the DW sweeps through the wire, reversing its magnetization. Nucleation pads are frequently used as part of nanowire devices and experimental structures. Magnetic-field-driven shift register memory can include an injection pad to write data while those attached to nanowire spiral turn sensors act as both a source and sink of domain walls. Both of these devices use two-dimensional wire circuits and therefore require the use of orthogonal in-plane magnetic fields to drive domain walls through wires of different orientations. These bi-axial fields can significantly alter the fields at which DW injection occurs and control the number of different injection modes. We have used magnetic transmission soft X-ray microscopy (M-TXM) [6] providing 25nm spatial resolution to image the evolution of magnetization configurations in patterned 24nm thick Ni{sub 80}Fe{sub 20} rectangular nucleation pads and attached wires during DW injection. The structures consisted of 2 {micro}m x 3 {micro}m nucleation pads with wires of width 200 nm, 300 nm or 500 nm attached Comparing the magnetic configuration of the injection pads with micromagnetic models, we find that the relative orientation of closure domains in the remanent magnetization configuration of injection pads determines the reversal pathway that follows, although this is further affected by applied transverse fields. Micromagnetic simulations were performed using a hybrid finite element/boundary element code. The magnetic elements were designed with 20 nm thickness and discretized into a mesh of tetrahedral elements with a maximum cell size of 20 nm. Material properties for bulk permalloy were used, i.e. exchange stiffness A = 1.3 x 10{sup -11} J/m, saturation magnetization M{sub S} = 800 kA/m, magneto-crystalline anisotropy K = 0 Jm{sup -3}, damping constant a = 0.01. A linearly increasing magnetic field (1 Oe/ns) was applied parallel to the wire long axis to simulate switching fields. The dimensions of the simulated structures mimicked the essential features of the experimental structures, although edge roughness was neglected from the model. The remanent magnetization state of the pad with no transverse field consists of a uniform magnetization aligned with the wire axis, with closure domains at the edges facing and joining the wire. When H{sub y} = 0 Oe and H{sub x} = 20 Oe, the magnetization state of the pad buckles, forming eight domains, half of which have magnetizations rotated away from the x-axis. As H{sub x} is increased, the rotation of the domains become larger and the non-rotated domains shrink A transverse field applied in addition to the axial field exhibits a more complex modes of magnetization reversal in the pad (Fig. 1). We understand the pathway of pad magnetization more generally by using micromagnetic simulations. Two initial configurations are shown in Fig. 2 with the closure domain on the left-hand edge of the pad either parallel or anti-parallel to both closure domains on the righthand edges of the pad. As H{sub x} is increased to inject a domain wall, the pad magnetization states changed to vortex states, as observed by M-TXM. At higher fields, the magnetization of the modeled pad became single-domain, although closure domains remained at fields up to H{sub x} = 90 Oe. This supports the suggestion that experimentally observed multi-modal injection is due to the magnetization state of the pad. In summary, the relative orientation of closure domains in the pads determines the magnetization reversal pathway under an axial field. However, the addition of transverse fields can alter these and lead to the pads undergoing reversal under lower axial fields. Our observations have wider implications for experiments and devices using patterned magnetic wires

Legionella pneumophila strain 130b possesses a unique combination of type IV secretion systems and novel Dot/Icm secretion system effector proteins

Legionella pneumophila is a ubiquitous inhabitant of environmental water reservoirs. The bacteria infect a wide variety of protozoa and, after accidental inhalation, human alveolar macrophages, which can lead to severe pneumonia. The capability to thrive in phagocytic hosts is dependent on the Dot/Icm type IV secretion system (T4SS), which translocates multiple effector proteins into the host cell. In this study, we determined the draft genome sequence of L. pneumophila strain 130b (Wadsworth). We found that the 130b genome encodes a unique set of T4SSs, namely, the Dot/Icm T4SS, a Trb-1-like T4SS, and two Lvh T4SS gene clusters. Sequence analysis substantiated that a core set of 107 Dot/Icm T4SS effectors was conserved among the sequenced L. pneumophila strains Philadelphia-1, Lens, Paris, Corby, Alcoy, and 130b. We also identified new effector candidates and validated the translocation of 10 novel Dot/Icm T4SS effectors that are not present in L. pneumophila strain Philadelphia-1. We examined the prevalence of the new effector genes among 87 environmental and clinical L. pneumophila isolates. Five of the new effectors were identified in 34 to 62% of the isolates, while less than 15% of the strains tested positive for the other five genes. Collectively, our data show that the core set of conserved Dot/Icm T4SS effector proteins is supplemented by a variable repertoire of accessory effectors that may partly account for differences in the virulences and prevalences of particular L. pneumophila strains. Copyright © 2010, American Society for Microbiology. All Rights Reserved

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations