Will savings from biosimilars offset increased costs related to dose escalation? A comparison of infliximab and golimumab for rheumatoid arthritis

INTRODUCTION: Biosimilar infliximab has the potential for appreciable cost savings compared to its reference biologic, but dose escalation is common and increases costs. We compared frequency of dose escalation and associated Medicare-approved amount so as to determine the break-even point at which infliximab dose escalation would offset the cost savings of using a biosimilar, referent to alternatively using golimumab. METHODS: We studied Medicare enrollees with rheumatoid arthritis (RA) initiating infliximab or golimumab. Frequency of dose escalation was summarized descriptively over 18 months, as were Medicare-approved amounts for reimbursement. Analyses were repeated conditioning on high adherence (i.e., non-discontinuation, \u3e 10-week gap). Multivariable-adjusted logistic regression and mixed models evaluated factors associated with infliximab dose escalation. RESULTS: A total of 5174 infliximab and 2843 golimumab initiators were observed. Dose escalation was rare for golimumab (5%) but common for infliximab (49%), and was even more common (72%) for infliximab among patients who persisted on treatment. Regardless of dose escalation, the adjusted least square mean dollar amounts were appreciably higher for golimumab ($28,146) than for infliximab ($21,216) and greater among persistent patients (cost difference $9269, favoring infliximab). Only when patients escalated infliximab to \u3e /= 8 mg/kg every 6 weeks was golimumab IV at break-even or less expensive. After controlling for multiple factors, physician ownership of the infusion center was associated with greater likelihood of infliximab dose escalation (odds ratio = 1.25, 95% CI 1.09-1.44). CONCLUSION: Despite frequent dose escalation with infliximab that often increase its dose by threefold or more, the savings from the current price of its biosimilar substantially offsets the costs of an alternative infused TNFi biologic for which no biosimilar is available

Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation

In the mammary gland Bcl-x is the most abundant cell survival factor from the Bcl-2 family. Since Bcl-x null mice die around day 12 of embryogenesis, the relevance of this protein in organ development and function is poorly understood. In erythroid cells bcl-x gene expression is controlled by cytokines and the transcription factor Stat5 (signal transducer and activator of transcription). However, we identified that bcl-x RNA levels in mammary tissue from prolactin receptor- and Stat5-null mice were indistinguishable from wild type mice. We have proposed that Bcl-x might control the survival of mammary epithelial cells throughout pregnancy, lactation, and the early stages of involution, and we have now tested this hypothesis through the conditional deletion of the bcl-x gene from mouse mammary epithelium. Conditional (floxed) bcl-x alleles were excised from alveolar cells during pregnancy using a Cre transgene under the control of the whey acidic protein gene promoter. Deletion of the bcl-x gene from the entire epithelial compartment (ducts and alveoli) was achieved by expressing Cre-recombinase under control of the mouse mammary tumor virus long terminal repeat. The absence of Bcl-x did not compromise proliferation and differentiation of mammary ductal and alveolar epithelial cells in virgin mice and during pregnancy and lactation. However, epithelial cell death and tissue remodeling were accelerated in the bcl-x conditional knockout mice during the first stage of involution. Concomitant deletion of the bax gene did not significantly modify the Bcl-x phenotype. Our results suggest that Bcl-x is not essential during mammopoiesis, but is critical for controlled apoptosis during the first phase of involution. Published by Elsevier Science Ireland Ltd

Plant Virus Biodiversity and Ecology

The Plant Virus Biodiversity and Ecology (PVBE) project has been initiated to survey the biodiversity of viruses affecting vascular plants

Maser threshold characterization by resonator Q-factor tuning

Whereas the laser is nowadays an ubiquitous technology, applications for its microwave analog, the maser, remain highly specialized, despite the excellent low-noise microwave amplification properties. The widespread application of masers is typically limited by the need of cryogenic temperatures. The recent realization of a continuous-wave room-temperature maser, using NV− centers in diamond, is a first step towards establishing the maser as a potential platform for microwave research and development, yet its design is far from optimal. Here, we design and construct an optimized setup able to characterize the operating space of a maser using NV− centers. We focus on the interplay of two key parameters for emission of microwave photons: the quality factor of the microwave resonator and the degree of spin level-inversion. We characterize the performance of the maser as a function of these two parameters, identifying the parameter space of operation and highlighting the requirements for maximal continuous microwave emission

Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)

OBJECTIVES: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-alpha (IL-6Ralpha), in patients with ankylosing spondylitis (AS). METHODS: Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety. RESULTS: Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints.The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred. CONCLUSIONS: The ALIGN study shows that IL-6Ralpha blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile

Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year

INTRODUCTION: Clinical trials of new treatments for rheumatoid arthritis (RA) typically require subjects to have an elevated acute phase reactant (APR), in addition to tender and swollen joints. However, despite the elevation of individual components of the Clinical Disease Activity Index (CDAI) (tender and swollen joint counts and patient and physician global assessment), some patients with active RA may have normal erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels and thus fail to meet entry criteria for clinical trials. We assessed the relationship between CDAI and APRs in the Consortium of Rheumatology Researchers of North America (CORRONA) registry by comparing baseline characteristics and one-year clinical outcomes of patients with active RA, grouped by baseline APR levels. METHODS: This was an observational study of 9,135 RA patients who had both ESR and CRP drawn and a visit at which CDAI was \u3e 2.8 (not in remission). RESULTS: Of 9,135 patients with active RA, 58% had neither elevated ESR nor CRP; only 16% had both elevated ESR and CRP and 26% had either ESR or CRP elevated. Among the 4,228 patients who had a one-year follow-up visit, both baseline and one-year follow-up modified Health Assessment Questionnaire (mHAQ) and CDAI scores were lowest for patients with active RA but with neither APR elevated; both mHAQ and CDAI scores increased sequentially with the increase in number of elevated APR levels at baseline. Each individual component of the CDAI followed the same trend, both at baseline and at one-year follow-up. The magnitude of improvement in both CDAI and mHAQ scores at one year was associated positively with the number of APRs elevated at baseline. CONCLUSIONS: In a large United States registry of RA patients, APR levels often do not correlate with disease activity as measured by joint counts and global assessments. These data strongly suggest that it is appropriate to obtain both ESR and CRP from RA patients at the initial visit. Requiring an elevation in APR levels as a criterion for inclusion of RA patients in studies of experimental agents may exclude some patients with active disease

Continuous-wave room-temperature diamond maser

The maser, older sibling of the laser, has been confined to relative obscurity due to its reliance on cryogenic refrigeration and high-vacuum systems. Despite this it has found application in deep-space communications and radio astronomy due to its unparalleled performance as a low-noise amplifier and oscillator. The recent demonstration of a room-temperature solid- state maser exploiting photo-excited triplet states in organic pentacene molecules paves the way for a new class of maser that could find applications in medicine, security and sensing, taking advantage of its sensitivity and low noise. However, to date, only pulsed operation has been observed in this system. Furthermore, organic maser molecules have poor thermal and mechanical properties, and their triplet sub-level decay rates make continuous emission challenging: alternative materials are therefore required. Therefore, inorganic materials containing spin-defects such as diamond and silicon carbide have been proposed. Here we report a continuous-wave (CW) room-temperature maser oscillator using optically pumped charged nitrogen-vacancy (NV) defect centres in diamond. This demonstration unlocks the potential of room-temperature solid-state masers for use in a new generation of microwave devices.Comment: 7 pages, 4 figure

Network Discovery Pipeline Elucidates Conserved Time-of-Day–Specific cis-Regulatory Modules

Correct daily phasing of transcription confers an adaptive advantage to almost all organisms, including higher plants. In this study, we describe a hypothesis-driven network discovery pipeline that identifies biologically relevant patterns in genome-scale data. To demonstrate its utility, we analyzed a comprehensive matrix of time courses interrogating the nuclear transcriptome of Arabidopsis thaliana plants grown under different thermocycles, photocycles, and circadian conditions. We show that 89% of Arabidopsis transcripts cycle in at least one condition and that most genes have peak expression at a particular time of day, which shifts depending on the environment. Thermocycles alone can drive at least half of all transcripts critical for synchronizing internal processes such as cell cycle and protein synthesis. We identified at least three distinct transcription modules controlling phase-specific expression, including a new midnight specific module, PBX/TBX/SBX. We validated the network discovery pipeline, as well as the midnight specific module, by demonstrating that the PBX element was sufficient to drive diurnal and circadian condition-dependent expression. Moreover, we show that the three transcription modules are conserved across Arabidopsis, poplar, and rice. These results confirm the complex interplay between thermocycles, photocycles, and the circadian clock on the daily transcription program, and provide a comprehensive view of the conserved genomic targets for a transcriptional network key to successful adaptation

HES5 silencing is an early and recurrent change in prostate tumourigenesis.

Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.The authors are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. They also thank the NIHR Cambridge Biomedical Research Centre, the DOH HTA (ProtecT grant), and the NCRI/MRC (ProMPT grant) for help with the bio-repository, The University of Cambridge, Hutchison Whampoa Limited and Cancer Research UK for funding. They are grateful to the CRUK Cambridge Institute Genomics and Bioinformatics Core Facilities. Cross-validation of HES5 methylation includes the use of data generated by the TCGA Research Network.This is the final version of the article. It was originally published in the Endocrine-Related Cancer, April 1, 2015 22 131-144 doi: 10.1530/ERC-14-0454