Correction to: Cost Effectiveness of Cladribine Tablets for the Treatment of Relapsing-Remitting Multiple Sclerosis in The Netherlands.

The second author's name should be "Maria De Francesco" rather than "Maria de Fransesco".

Cost Effectiveness of Cladribine Tablets for the Treatment of Relapsing-Remitting Multiple Sclerosis in The Netherlands.

BACKGROUND: Cladribine tablets have recently become available in The Netherlands for patients with relapsing-remitting multiple sclerosis (RRMS) as a disease-modifying agent that reduces the frequency and severity of relapses and delays disability progression. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of cladribine tablets, compared with alternative options, in the treatment of RRMS patients with high disease activity (HDA) and patients with rapidly evolving severe (RES) MS in The Netherlands. METHODS: A Markov model was developed simulating the costs and effects of RRMS treatment. For HDA, alemtuzumab and fingolimod were used as comparators; natalizumab was used for the RES subpopulation. The analysis included a societal perspective and a value-of-information (VOI) analysis. RESULTS: For the HDA subpopulation, treatment with cladribine tablets was the cost-effective (dominant) strategy compared with alemtuzumab and fingolimod, with 50.9% and 98.2%, respectively, probability of being cost effective at a threshold of €50,000/QALY gained and a net monetary benefit (NMB) of €10,866 and €151,115, respectively. For the RES subpopulation, treatment with cladribine tablets dominated treatment with natalizumab, with 94.1% probability of being cost effective at a threshold of €50,000/QALY gained and an NMB of €122,986. Note that these outcomes are driven by the lower costs of cladribine tablets. Efficacy differences were small, very uncertain, and likely not clinically meaningful. The probabilistic sensitivity analyses showed significant overlap in the credible intervals for total lifetime QALY outcomes and costs of cladribine tablets and all relevant comparators. The population-level VOI amounted to €19,295,441. CONCLUSIONS: The base-case analysis shows that treatment of RRMS with cladribine tablets is cost effective versus alemtuzumab and fingolimod in HDA patients, and cost effective versus natalizumab in RES patients, at a threshold of €50,000. Driven by the lower costs, cladribine tablets were cost effective (dominant) in all base-case analyses. However, given that outcomes are based on indirect comparisons and post hoc subgroup analysis, as well as the uncertainty surrounding the outcomes, the results presented in this paper should be interpreted with caution.

Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA). METHODS: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety. RESULTS: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs. CONCLUSION: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.

Osteoporotic fractures: a systematic review of U.S. healthcare costs and resource utilization.

Osteoporotic fractures are costly in terms of both the dollar amount and healthcare utilization. The objective of this review was to systematically synthesize published evidence regarding direct costs associated with the treatment of osteoporosis-related fractures in the U.S. We conducted a systematic literature review of published studies that used claims databases and economic studies reporting costs associated with osteoporosis-related fractures in the U.S. Studies published between 1990 and 2011 were systematically searched in PubMed (primary source), Ovid HealthSTAR, EMBASE and the websites of large agencies. Data concerning study design, patient population and cost components assessed were extracted with qualitative assessment of study methods, limitations and conclusions. Cost assessment included direct medical and hospitalization (inpatient) costs. The cost differences by age and gender were examined. Of the 33 included studies, 26 reported an estimated total medical cost and hospital resource use associated with osteoporotic fractures. These studies indicated that, in the year following a fracture, medical and hospitalization costs were 1.6-6.2 higher than pre-fracture costs and 2.2-3.5 times higher than those for matched controls. Analysis of the hospitalization costs by osteoporotic fracture type resulted in hip fractures identified as the most expensive fracture type (unit cost range $US 8358-32195), while wrist and forearm fractures were the least expensive (unit cost range $US 1885-12136). Although incremental fracture costs were generally lower in the elderly than in the younger population, total costs were highest for the older (≥65 years of age) population. Total healthcare costs for fractures were highest for the older female population, but unit fracture costs in women were not consistently found to be higher than for men. The qualitative assessment of the included studies demonstrated that the design and reporting of individual studies were of good quality. However, the findings of this review and comparisons across studies were limited by differences in methodologies used by the different studies to derive costs, the populations included in the studies used and the fracture assessment. Despite the variability in estimates, the literature indicates that osteoporosis-related fractures are associated with high total medical and hospitalization costs in the U.S. The variability in the cost estimates highlights the importance of comparing the methodologies and the types of costs used when choosing an appropriate unit cost for economic modelling.

Changing epidemiology of meningococcal disease in Europe from the mid-20th to the early 21st Century.

The epidemiology of meningococcal disease in Europe since 1945 has shown fluctuations in incidence, serogroup distribution and case-fatality rate. Outbreaks and epidemics driven by the introduction of new virulent strains into Europe have occurred unpredictably. Epidemics associated with serogroups A and B have occurred in all regions of the continent. Additionally, there have been periods of increased outbreak frequency, such as those associated with serogroup C in the 1980s and 1990s, against an endemic disease incidence of around one to two cases per 100,000 population. Serogroup W135 disease was observed in the 1970s and again in 2000, while serogroup Y has recently emerged in Sweden and the Czech Republic. This article describes the changing epidemiology of meningococcal disease in Europe. An understanding of this is important for informed decision-making about different meningococcal vaccines that may be considered for use in Europe.

Pregabalin, the lidocaine plaster and duloxetine in patients with refractory neuropathic pain: a systematic review.

BACKGROUND: Patients frequently fail to receive adequate pain relief from, or are intolerant of, first-line therapies prescribed for neuropathic pain (NeP). This refractory chronic pain causes psychological distress and impacts patient quality of life. Published literature for treatment in refractory patients is sparse and often published as conference abstracts only. The aim of this study was to identify published data for three pharmacological treatments: pregabalin, lidocaine plaster, and duloxetine, which are typically used at 2(nd) line or later in UK patients with neuropathic pain. METHODS: A systematic review of the literature databases MEDLINE, EMBASE and CCTR was carried out and supplemented with extensive conference and grey literature searching. Studies of any design (except single patient case studies) that enrolled adult patients with refractory NeP were included in the review and qualitatively assessed. RESULTS: Seventeen studies were included in the review: nine of pregabalin, seven of the lidocaine plaster, and one of duloxetine. No head-to-head studies of these treatments were identified. Only six studies included treatments within UK licensed indications and dose ranges. Reported efficacy outcomes were not consistent between studies. Pain scores were most commonly assessed in studies including pregabalin; trials of pregabalin and the lidocaine plaster reported the proportion of responders. Significant improvements in the total, sensory and affective scores of the Short-form McGill Pain Questionnaire, and in function interference, sleep interference and pain associated distress, were associated with pregabalin treatment; limited or no quality of life data were available for the other two interventions. Limitations to the review are the small number of included studies, which are generally small, of poor quality and heterogeneous in patient population and study design. CONCLUSIONS: Little evidence is available relevant to the treatment of refractory neuropathic pain despite the clinical need. There is a notable lack of high-quality comparative studies. It is evident that there is a need for future, high quality trials, particularly "gold-standard" RCTs in this refractory patient population.

Quantitation of ovine cytokine mRNA by real-time RT-PCR.

In this study we describe for the first time the dynamics of the expression of the cytokines, IL-1beta, IL-12p40, TNFalpha in ovine dendritic cells and macrophages after LPS stimulation. Real time RT-PCR was used for the quantitation of these cytokines and IL-4 and IFNgamma as well as two potential housekeeping genes (HKG), ATPase and GAPDH, in mRNAs from ovine leucocyte populations. Both dual-labelled probes (TAMRA/FAM) and SYBR Green assays were utilised, using a Corbett Research RotorGene and ABI 7700 machine. In order to quantitate each cytokine in our assays all C(T) values were compared to a standard curve generated using plasmid DNA containing the cytokine of interest. To validate our assays, concanavalin A-stimulated peripheral blood mononuclear cells (PBMCs) and LPS-stimulated monocyte-derived dendritic cells (MoDC) and monocyte-derived macrophages (MDMØ) were examined. We found that peak cytokine mRNA expression was between 3 and 6 h for the cytokines examined except for IL-12p40 where peak cytokine release was around 12 h post-stimulation in MDMØ and PBMCs. However, in MoDCs, peak IL-12p40 mRNA expression was observed within 3-6 h. We have identified a sensitive and reliable method for the identification of ovine cytokine mRNAs.

Identification of an S-adenosylhomocysteine hydrolase-like transcript induced during dendritic cell differentiation.

Dendritic cells (DC) are the professional antigen-presenting cells that initiate immune responses. While DC take up antigen, migrate to lymph nodes and present processed antigen to T lymphocytes, little is known of the intracellular biochemical pathways controlling these events. Using the differential display technique, employing the activated blood DC-like cell line L428, we isolated a cDNA induced during DC differentiation likely to have a regulatory function. This cDNA encoded a putative 530-amino-acid (aa) protein consisting of a unique hydrophilic domain (106 aa) and a domain (424 aa) similar to the methylation pathway enzyme S-adenosylhomocysteine hydrolase (AHCY). Therefore, this molecule was termed DC-expressed AHCY-like molecule (DCAL). DCAL mRNA was expressed moderately in fresh blood DC, but was not detectable in other peripheral blood mononuclear cells. DCAL mRNA increased markedly during activation of blood and skin DC (Langerhans cells), but was diminished in terminally differentiated tonsil DC. Cultured monocytes expressed little DCAL mRNA, but levels increased markedly when differentiated into DC by cytokines GM-CSF and IL-4. The DCAL gene [Chromosome (Chr) 1] and another previously identified DCAL-like molecule KIAA0828 (Chr 7) differed from the AHCY gene (Chr 20) in gene organization. Thus, DCAL may have a role in controlling critical events in DC differentiation and belong to a novel family of AHCY-like molecules.