Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is an inborn error of immunity (IEI) caused by a dominant-negative mutation in the signal transducer and activator of transcription 3 (STAT 3). This disease is characterized by chronic eczematoid dermatitis, recurrent staphylococcal skin abscesses, pneumonia, pneumatoceles, and extremely high serum IgE levels. Loss-of-function STAT3 mutations may also result in distinct non-immunologic features such as dental, facial, skeletal, and vascular abnormalities, central nervous system malformations and an increased risk for bone fractures. Prophylactic treatment of Candida infections and prophylactic antimicrobial therapy for staphylococcal skin infections and sinopulmonary infections are essential. An awareness of the oral and maxillofacial features of HIES may facilitate early diagnosis with genetic counselling and may improve future patient care. This study describes oral, dental, and maxillofacial manifestations in 14 patients with genetically defined AD-HIES. We also review the literature and propose recommendations for the complex care of patients with this rare primary immunodeficiency.

[The importance of patient reported outcome measures in Pompe disease]. / A betegek által riportált kimeneti mutatók jelentosége Pompe-kórban.

BACKGROUND AND PURPOSE: In recent decades it has become increasingly important to involve patients in their diagnostic and treatment process to improve treatment outcomes and optimize compliance. By their involvement, patients can become active participants in therapeutic developments and their observations can be utilized in determining the unmet needs and priorities in clinical research. This is especially true in rare diseases such as Pompe disease. Pompe disease is a genetically determined lysosomal storage disease featuring severe limb-girdle and axial muscle weakness accompanied with respiratory insufficiency, in which enzyme replacement therapy (ERT) now has been available for 15 years. METHODS: In our present study, patient reported outcome measures (PROMs) for individuals affected with Pompe disease were developed which included questionnaires assessing general quality of life (EuroQoL, EQ-5D, SF36), daily activities and motor performance (Fatigue Severity Score, R-PAct-Scale, Rotterdam and Bartel disability scale). Data were collected for three subsequent years. The PROM questionnaires were a good complement to the physician-recorded condition assessment, and on certain aspects only PROMs provided information (e.g. fatigue in excess of patients' objective muscle weakness; deteriorating social activities despite stagnant physical abilities; significant individual differences in certain domains). The psychological effects of disease burden were also reflected in PROMs. RESULTS: In addition to medical examination and certain endpoints monitored by physicians, patient perspectives need to be taken into account when assessing the effectiveness of new, innovative treatments. With involvement of patients, information can be obtained that might remain uncovered during regular medical visits, although it is essential in determining the directions and priorities of clinical research. CONCLUSION: For all orphan medicines we emphasize to include patients in a compulsory manner to obtain general and disease-specific multidimensional outcome measures and use them as a quality indicator to monitor treatment effectiveness.

[Oral manifestations in patients with primary immunodeficiencies]. / Szájüregi manifesztációk primer immundeficientiákban.

Characteristic lesions of the oral cavity in primary immunodeficiencies are commonly found in the form of periodontal disease, tooth decay and disorders of the oral mucosa. Humoral immunodeficiencies may cause tooth decay, while severe forms of plaque-induced periodontal disease are common in phagocytic deficiencies. The structural abnormalities of the teeth can occur in immunodeficiencies associated with apoptosis defect. Oral squamous cell carcinoma is a possible complication of immunodeficiencies associated with DNA repair defects. Orv Hetil. 2018; 159(49): 2079-2086.

The European challenges of funding orphan medicinal products.

BACKGROUND: Funding of orphan medicinal products (OMPs) is an increasing challenge in the European Union (EU). OBJECTIVES: To identify the different methods for public funding of OMPs in order to map the availability for rare disease patients, as well as to compare the public expenditures on OMPs in 8 EU member states. METHODS: Information on the reimbursement status of 83 OMPs was collected in 8 countries by distinguishing standard and special reimbursements. In two consecutive years, the total public expenditures on OMPs were calculated by using annual EUR exchange rates. Annual total public expenditures were calculated per capita, and as a proportion of GDP, total public pharmaceutical and healthcare budgets. Differences between countries were compared by calculating the deviations from the average spending of countries. RESULTS: In 2015 29.4-92.8% of the 83 OMPs were available with any kind of public reimbursement in participant countries including special reimbursement on an individual basis. In Austria, Belgium and France more OMPs were accessible for patients with public reimbursement than in Bulgaria, Czech Republic, Hungary and Poland. Standard reimbursement through retail pharmacies and/or hospitals was applied from 0 to 41% of OMPs. The average annual total public expenditure ranged between 1.4-23.5 €/capita in 2013 and 2014. Higher income countries spent more OMPs in absolute terms. Participant countries spent 0.018-0.066% of their GDPs on funding OMPs. Average expenditures on OMPs were ranged between 2.25-6.51% of the public pharmaceutical budget, and 0.44-0.96% of public healthcare expenditures. CONCLUSIONS: Standard and special reimbursement techniques play different roles in participant countries. The number of accessible OMPs indicated an equity gap between Eastern and Western Europe. The spending on OMPs as a proportion of GDP, public pharmaceutical and healthcare expenditure was not higher in lower income countries, which indicates substantial differences in patient access to OMPs in favour of higher-income countries. Equity in access for patients with rare diseases is an important policy objective in each member state of the EU; however, equity in access should be harmonized at the European level.

[DISEASE BURDEN OP DUCHENNE MUSCULAR DYSTROPHY PATIENTS AND THEIR CAREGIVERS]. / DUCHENNE-FÉLE IZOMDISZTRÓFIÁVAL ÉLO BETEGEK ÉS GONDOZÓIK BETEGSÉGTERHEI.

BACKGROUND AND PURPOSE: Data on the disease burden of Duchenne Muscular Dystrophy are scarce in Hungary. The aim of this study was to assess patients' and their caregivers' health related quality of life and healthcare utilisations. METHODS: A cross sectional survey was performed as part of the European BURQOL-RD project. The EQ-5D-5L and Barthel Index questionnaires were applied, health care utilisations and patients' informal carers were surveyed. RESULTS: One symptomatic female carer, 50 children (boys 94%) and six adult patients (five males) participated in the study, the latter two subgroups were included in the analysis. The average age was 9.7 (SD = 4.6) and 24.3 (SD = 9.8) years, respectively. Median age at time of diagnosis was three years. The average EQ-5D score among children and adults was 0.198 (SD = 0.417) and 0.244 (SD = 0.322), respectively, the Barthel Index was 57.6 (SD = 29.9) and 53.0 (SD = 36.5). Score of satisfaction with healthcare (10-point Likert-scale) was mean 5.3 (SD = 2.1) and 5.3 (SD = 2.9). 15 children were hospitalised in the past 12 months for mean 12.9 (SD = 24.5) days. Two patients received help from professional carer. 25 children (mean age 11.1, SD = 4.4 years) were helped/supervisied by principal informal carer (parent) for mean 90.1 (SD = 44.4) hours/week and further family members helped in 21 cases. Correlation between EQ-5D and Barthel Index was strong and significant (0.731; p < 0.01) as well as with informal care time (-0.770; p < 0.01), but correlation with satisfaction with health care was not significant (EQ-5D: 0.241; Barthel Index: 0.219; informal care: -0.142). CONCLUSION: Duchenne muscular dystrophy leads to a significant deterioration in the quality of life of patients. Parents play outstanding role in the care of affected children. This study is the first in the Central and Eastern European region that provides quality of life data in this rare disease for further health economic studies.

Systematic review on the evaluation criteria of orphan medicines in Central and Eastern European countries.

BACKGROUND: In case of orphan drugs applicability of the standard health technology assessment (HTA) process is limited due to scarcity of good clinical and health economic evidence. Financing these premium priced drugs is more controversial in the Central and Eastern European (CEE) region where the public funding resources are more restricted, and health economic justification should be an even more important aspect of policy decisions than in higher income European countries. OBJECTIVES: To explore and summarize the recent scientific evidence on value drivers related to the health technology assessment of ODs with a special focus on the perspective of third party payers in CEE countries. The review aims to list all potentially relevant value drivers in the reimbursement process of orphan drugs. METHODS: A systematic literature review was performed; PubMed and Scopus databases were systematically searched for relevant publications until April 2015. Extracted data were summarized along key HTA elements. RESULTS: From the 2664 identified publications, 87 contained relevant information on the evaluation criteria of orphan drugs, but only 5 had direct information from the CEE region. The presentation of good clinical evidence seems to play a key role especially since this should be the basis of cost-effectiveness analyses, which have more importance in resource-constrained economies. Due to external price referencing of pharmaceuticals, the relative budget impact of orphan drugs is expected to be higher in CEE than in Western European (WE) countries unless accessibility of patients remains more limited in poorer European regions. Equity principles based on disease prevalence and non-availability of alternative treatment options may increase the price premium, however, societies must have some control on prices and a rationale based on multiple criteria in reimbursement decisions. CONCLUSIONS: The evaluation of orphan medicines should include multiple criteria to appropriately measure the clinical added value of orphan drugs. The search found only a small number of studies coming from CEE, therefore European policies on orphan drugs may be based largely on experiences in WE countries. More research should be done in the future in CEE because financing high-priced orphan drugs involves a greater burden for these countries.

[Shift of focus in the financing of Hungarian drugs. Reimbursement for orphan drugs for treating rare diseases: financing of enzyme replacement therapy in Hungary]. / Hangsúlyeltolódások a hazai gyógyszerek finanszírozásában. A ritka betegségek kezelésére szolgáló árva gyógyszerek támogatása. Enzimpótló kezelések finanszírozása hazánkban.

Focusing on the benefits of patients with rare disease the authors analysed the aspects of orphan medicines financed in the frame of the Hungarian social insurance system in 2012 in order to make the consumption more rational, transparent and predictable. Most of the orphan drugs were financed in the frame of compassionate use by the reimbursement system. Consequently, a great deal of crucial problems occurred in relation to the unconventional subsidized method, especially in the case of the highest cost enzyme replacement therapies. On the base of the findings, proposals of the authors are presented for access to orphan drugs, fitting to the specific professional, economical and ethical aspects of this unique field of the health care system. The primary goal is to provide a suitable subsidized method for the treatment of rare disease patients with unmet medical needs. The financial modification of orphans became indispensible in Hungary. Professionals from numerous fields dealing with rare disease patients' care expressed agreement on the issue. Transforming the orphan medicines' financial structure has been initiated according to internationally shared principles.