Targeted review of IL36RN mutations in patients with generalised pustular psoriasis.

Background: Generalised pustular psoriasis (GPP) is a rare and chronic skin disease historically treated with therapies that were originally intended to treat plaque psoriasis (PsO). However, GPP and plaque PsO have distinct pathogeneses and clinical courses. Objectives: This study aimed to further characterise the unique genetic background of GPP by summarising evidence on the frequency and type of IL36RN gene mutation, a gene that normally suppresses proinflammatory responses, in patients with GPP compared to patients with GPP and plaque PsO, and patients with plaque PsO only. Methods and Results: A targeted literature review was conducted to identify studies reporting IL36RN mutations and/or HLA-Cw6 allele frequency in patients with GPP. Meta-analyses showed a significantly higher rate of IL36RN mutations in the GPP-only population compared to the GPP + plaque PsO population (OR 3.51; 95% CI 2.29, 5.38). Monoallelic mutations of IL36RN were found in up to 33.3%, and biallelic mutations in up to 73.2% of patients with GPP (GPP-only and GPP + plaque PsO), in contrast with mono- and biallelic frequencies of only 0%-11.9% and 0%, respectively, in patients with plaque PsO only. Mean age-of-onset ranged from 5.9 to 48.9 years old, with most studies reporting a GPP age-of-onset between 20 and 40 years old. Twenty-one mutations were identified in the biallelic state and three in monoallelic. The most reported mutations were c.115 + 6T > C (p. Arg10ArgfsX1) (18 studies); c.227 C > T (p.Pro76Leu) (10 studies); and c.338 C > T (p.Ser113Leu) (8 studies). Mutations varied depending on geography and ethnicity, with the most frequently reported mutation predominantly reported in East Asian studies and international studies that included Asian patients. Rates of HLA-Cw6, the risk allele most strongly associated with plaque PsO, were 0%-28.6% for patients with GPP, similar to rates in the general population (10.5%-20%). Conclusion: Considering the differences between GPP and plaque PsO in aetiology and disease symptoms, effective, GPP-specific treatment options are needed, and recent research suggests that blockade of IL-36 signalling may be an effective target for treatment of GPP.

Pancreatic enzyme replacement therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis: a 1-year disease management study on symptom control and quality of life.

OBJECTIVE: Exocrine pancreatic insufficiency (EPI) is frequent in patients with chronic pancreatitis (CP). This 1-year, prospective, multicenter, observational, disease management study aimed to assess symptom improvement and quality of life in patients with CP with EPI who were receiving pancreatic enzyme replacement. METHODS: Patients with CP and chronic EPI were either assigned to cohort 1 that consisted of patients already taking pancreatin (Kreon; Abbott Arzneimittel GmbH, Hannover, Germany) or cohort 2 that consisted of patients with newly diagnosed EPI without prior pancreatic enzyme treatment. Symptoms were documented, and quality of life was assessed using the gastrointestinal quality of life index (GIQLI) at baseline, 6 months, and 1 year. RESULTS: A total of 294 patients were evaluated (cohort 1, n = 206; cohort 2, n = 88). The proportion of patients experiencing gastrointestinal symptoms and recurrent pain after 1 year was significantly reduced in both cohorts (P < 0.001). The alleviation of symptoms was reflected in GIQLI score improvements at 1 year in both cohorts (P < 0.001), independent of CP severity and etiology. Improvements in GIQLI score were more pronounced in cohort 2 (P < 0.001). CONCLUSIONS: Pancreatin demonstrated symptom relief and improvement in quality of life in patients with CP-related EPI in this disease management study.

Reducing uncertainty in value-based pricing using evidence development agreements: the case of continuous intraduodenal infusion of levodopa/carbidopa (Duodopa®) in Sweden.

BACKGROUND: Value-based pricing (VBP), whereby prices are set according to the perceived benefits offered to the consumer at a time when costs and benefits are characterized by considerable uncertainty and are then reviewed ex post, is a much discussed topic in pharmaceutical reimbursement. It is usually combined with coverage with evidence development (CED), a tool in which manufacturers are granted temporary reimbursement but are required to collect and submit additional health economic data at review. Many countries, including the UK, are signalling shifts in this direction. Several countries, including Sweden, have already adopted this approach and offer good insight into the benefits and pitfalls in actual practice. OBJECTIVE: To describe VBP reimbursement decision making using CED in actual practice in Sweden. METHODS: Decision making by The Dental and Pharmaceutical Benefits Agency (TLV) in Sweden was reviewed using a case study of continuous intraduodenal infusion of levodopa/carbidopa (Duodopa®) in the treatment of advanced Parkinson's disease (PD) with severe motor fluctuations. RESULTS: The manufacturer of Duodopa® applied for reimbursement in late 2003. While the proper economic data were not included in the submission, TLV granted reimbursement until early 2005 to provide time for the manufacturer to submit a formal economic evaluation. The re-submission with economic data was considered inadequate to judge cost effectiveness, so TLV granted an additional extension of reimbursement until August 2007, at which time conclusive data were expected. The manufacturer initiated a 3-year, prospective health economic study and a formal economic model. Data from a pre-planned interim analysis of the data were loaded into the model and the cost-effectiveness ratio was the basis of the next re-submission. TLV concluded that the data were suitable for making a definite decision and that the drug was not cost effective, deciding to discontinue reimbursement for any new patients (current patients were unaffected). The manufacturer continued to collect data and to improve the economic model and re-submitted in 2008. New data and the improved model resulted in reduced uncertainty and a lower cost-effectiveness ratio in the range of Swedish kronor (SEK)430,000 per QALY gained in the base-case analysis, ranging up to SEK900,000 in the most conservative sensitivity analysis, resulting in reimbursement being granted. DISCUSSION: The case of Duodopa® provides excellent insight into VBP reimbursement decision making in combination with CED and ex post review in actual practice. Publicly available decisions document the rigorous, time-consuming process (four iterations were required before a final decision could be reached). The data generated as part of the risk-sharing agreement proved correct the initial decision to grant limited coverage despite lack of economic data. Access was provided to 100 patients while evidence was generated. CONCLUSIONS: Economic appraisal differs from clinical assessment, and decision makers benefit from analysis of naturalistic, actual practice data. Despite reviewing the initial trial-based, 'piggy-back' economic analysis, TLV was uncertain of the cost effectiveness in actual practice and deferred a final decision until observational data from the DAPHNE study became available. Second, acceptance of economic modelling and use of temporary reimbursement conditional on additional evidence development provide a mechanism for risk sharing between TLV and manufacturers, which enabled patient access to a drug with proven clinical benefit while necessary evidence to support claims of cost effectiveness could be generated.

Cost-utility analysis of eprosartan compared to enalapril in primary prevention and nitrendipine in secondary prevention in Europe--the HEALTH model.

OBJECTIVE: To investigate the cost-utility of eprosartan versus enalapril (primary prevention) and versus nitrendipine (secondary prevention) on the basis of head-to-head evidence from randomized controlled trials. METHODS: The HEALTH model (Health Economic Assessment of Life with Teveten for Hypertension) is an object-oriented probabilistic Monte Carlo simulation model. It combines a Framingham-based risk calculation with a systolic blood pressure approach to estimate the relative risk reduction of cardiovascular and cerebrovascular events based on recent meta-analyses. In secondary prevention, an additional risk reduction is modeled for eprosartan according to the results of the MOSES study ("Morbidity and Mortality after Stroke--Eprosartan Compared to Nitrendipine for Secondary Prevention"). Costs and utilities were derived from published estimates considering European country-specific health-care payer perspectives. RESULTS: Comparing eprosartan to enalapril in a primary prevention setting the mean costs per quality adjusted life year (QALY) gained were highest in Germany (Euro 24,036) followed by Belgium (Euro 17,863), the UK (Euro 16,364), Norway (Euro 13,834), Sweden (Euro 11,691) and Spain (Euro 7918). In a secondary prevention setting (eprosartan vs. nitrendipine) the highest costs per QALY gained have been observed in Germany (Euro 9136) followed by the UK (Euro 6008), Norway (Euro 1695), Sweden (Euro 907), Spain (Euro -2054) and Belgium (Euro -5767). CONCLUSIONS: Considering a Euro 30,000 willingness-to-pay threshold per QALY gained, eprosartan is cost-effective as compared to enalapril in primary prevention (patients >or=50 years old and a systolic blood pressure >or=160 mm Hg) and cost-effective as compared to nitrendipine in secondary prevention (all investigated patients).

Establishing the health and economic impact of influenza vaccination within the European Union 25 countries.

BACKGROUND: In 2003, the World Health Assembly (WHA) issued a resolution for prevention and control of influenza pandemics and annual epidemics, which urges the European Union 25 (EU-25) Member States to (1) establish and implement strategies to increase vaccination coverage of all people at high risk, including the elderly and people with underlying disease, with the goal of attaining vaccination coverage of the elderly population of at least 50% by 2006 and 75% by 2010; (2) to assess the disease burden and economic impact of annual influenza epidemics as a basis for framing and implementing influenza prevention policies. This resolution was reinforced by the European Union (EU), where Member States agreed to make additional efforts to improve uptake on their territory in accordance with their own recommendations and to achieve the World Health Organisation (WHO) target of 75% in high risk groups before 2010. It was also noted that the changing demographic profile of the EU population would result in an increasing number of elderly people falling within the current target groups. OBJECTIVES: To establish the number of people who may be eligible for influenza vaccination in the EU, and estimate the costs and consequences of not vaccinating this population for five EU Member States, France, Germany, Italy, Spain, and the UK. METHODS: A mathematical model has previously been developed, in which vaccine distribution data are combined with demographic and health economics data to model the public health consequences of influenza and possible intervention strategies. We have extended that model using specific EU-25 demographic data on populations at risk of influenza during the inter-pandemic period. For each country, the total population and age breakdown was calculated to estimate the percentage of the population that falls under the WHA recommendations. Other target groups for influenza vaccination were identified by analysing estimating the proportion of the population with respiratory or cardiovascular related diseases, diabetes, AIDS or transplantation, as well as health care professionals. Target population size and possible vaccination coverage rates across the EU-25 Member States, along with the potential cost and health consequence impact is estimated. RESULTS: For the EU-25, it was estimated that up to 49.1% of the population (or 223.4 million people) should be vaccinated against influenza. This ranged from 41.6% in Cyprus to 56.4% in the UK. There were, on average, 174 vaccine doses distributed per 1000 population within the EU-25, which leads to an average vaccination rate of the target population of 35.4% based on current supply constraints. As a consequence, up to 144.4 million people who could be considered "at risk" may not currently be vaccinated. Implementing a 100% vaccination rate programme for all risk groups across the EU-25 would lead to an estimated reduction of number of influenza cases of 7.22 million, 1.96 million reduced PCP visits for influenza treatment, 796,743 less hospital admissions and 68,537 fewer influenza related deaths for all EU-25 countries. The implementation of a 100% vaccination rate programme for all risk groups in France, Germany, Italy, Spain and UK would require an additional 1.52 billion Euro. This would result in estimated savings of 39.45 million Euro of reduced primary care visits and further savings of 1.59 billion Euro in reduced hospitalisations respectively in these countries. CONCLUSIONS: There is a gap between current vaccination coverage and the EU recommendations. The public health consequences of low vaccination coverage include increased morbidity, hospitalisations and mortality associated with influenza-related complications. This model is a powerful tool to: (1) support EU public health officials in implementing recommendations; (2) to visualize the need for increased vaccination rates for better influenza control; (3) the consequences of low vaccine coverage.