Rare diseases: general principles, specific problems, and health interventions

Rare diseases are a large group of about 5000 diseases, 90% of which are genetically determined, which potentially involve all human organs and are characterized by a low prevalence in the population; this is frequently associated to problems in achieving a rapid and correct diagnosis and an adequate treatment. Up to now, a generally accepted definition or classification of rare diseases is not available. The Programme of Community Action 1999-2003 on rare diseases within the framework for action in the field of public health gives the following definition for rare diseases: diseases with a prevalence in the European Union (EU) population of less than 5 per 10,000. Notwithstanding the low prevalence of each disorder, rare diseases are very numerous and, when considered overall, they are a significant public health problem in many countries (e.g. Italy, Europe, USA); in fact rare diseases are often chronic and invalidating or cause early mortality. In this report, we illustrate some general concepts and specific problems regarding rare diseases as well as public health activities being undertaken in the USA, EU and Italy.     

Seltene Krankheiten

Rare diseases are defined by lifetime prevalence and are a medically heterogeneous group. Treatment options and the state of knowledge about these diseases are also very heterogeneous, as well as the respective needs for research. This article provides an overview on funding programs in Germany, further examples of countries within Europe and the European Commission, and a few examples of research networks. It is one of the goals of the article to show similarities and differences between the funding programs. The funding organizations of most countries and the European Commission (FP7) fund research on rare diseases with programs in which researchers define the contents in bottom up approaches. While, in general, basic science is well established, the translation of knowledge into clinical benefit for the patients is slow. Because of the low prevalence and geographic distribution of patients and researchers, research on rare diseases suffers from infrastructural deficits. While France, Germany, Italy and Spain have implemented research programs which are specific for rare diseases and aim to support networking of scarce resources and to stimulate interdisciplinary collaborations, other countries fund research on rare diseases within the context of general programs.     

Rare Diseases: chronic diseases that need a new approach

The concept of Rare Diseases is relatively new. They are those processes "...that can be mortal or to cause a chronic weakening of the patient and who, due to its little prevalence, require combined efforts to treat them. For indicative purposes, a little prevalence is considered when is lesser than 5 cases per 10,000 people in the Community". The existence of these diseases is closely tied with orphan drugs, meaning all drugs, prosthesis, biological agents or dietetic preparations destined to the treatment of a Rare Disease. Besides, it is necessary to add two factors more: 1. The Primary Attention physicians do not feel very motivated in their knowledge and 2. These diseases need a complex sociosanitary attention, habitually more expensive than chronic diseases. By all exposed the Rare Diseases appear like a universe that requires a new sociosanitary approach from the health system.     

Review of Rare Diseases Resources: National Organization for Rare Disorders (NORD) Rare Disease Database,NIH Genetic and Rare Diseases Information Center,and Orphanet

This column profiles three important online resources for rare disorder information. The National Organization for Rare Disorders (NORD) Rare Disease Database set the standard for thorough, detailed monographs on rare diseases starting in the 1990s. The NORD Database is complemented by the National Institutes of Health (NIH) Genetic and Rare Diseases Information Center online and the European resource, Orphanet, both of which provide much broader coverage, if less in depth than NORD’s. Reading level for all three information sources is high, and there are occasional issues with currency. However, consumer health librarians should find these organizations’ web-based databases to be reliable sources of information on health conditions that can be perplexing for both patient and health care providers alike.     

某院2015年-2019年罕见病住院病例特征分析

目的分析陕西省某三甲综合医院2015年-2019年罕见病住院病例特征，为开展罕见病研究提供依据。方法根据《第一批罕见病目录》，收集医院2015年-2019年罕见病住院病例资料，进行回顾性分析。结果2015年-2019年医院共收住院罕见病患者1 055例次，占住院患者总例数的0.15%。罕见病病例数男女性别比为1.14:1；不同年龄段病例数分布依次为中年组＞青年组＞老年组＞儿童组；涉及21个疾病系统分类中的10个分类，其中神经系统疾病患者最多；共覆盖42种罕见病，前10位病种人数占患者总数的84.55%，前3位分别为肌萎缩侧索硬化、视神经脊髓炎、重症肌无力；从费用构成来看，前10位病种诊断费及药品费占比普遍较高，少数病种耗材费占比较高。重复住院率前10位的病种中，重复住院率在25%～64%。结论该院罕见病发病年龄跨度大、疾病类型多样、住院费用较高、个体差异较大，具有一定代表性，可为推动陕西省乃至西北地区罕见病研究提供参考。     

Legislation on professional respiratory diseases

The legally protected occupational pathology consists of work accidents and occupational diseases. Diseases are considered to be occupational when there is a relationship of demonstrable causality between exposure to a determinate occupational risk and a specific disease. To facilitate recognition, different organisations (International Labour Organisation, European Community) draw up, update and recommend the use of lists that are voluntarily adopted by member states. In the case of the Spanish state, the system of the closed list has been adopted. The current list was published in 1978 and the system of notification and registration currently in use is in need of urgent reform, which has been started. It is frequently difficult to identify the work-related origin of occupational diseases and they are often treated in the public health care system without their relation to work being recognised. Knowledge of some basic aspects of the labour legislation by the health workers and the inclusion of a few questions during the anamnesis of patients would make their identification and adequate treatment possible.     

A cross-national comparative study of orphan drug policies in the United States, the European Union, and Japan: towards a made-in-China orphan drug policy

Rare diseases can severely impact patient life quality as well as impose a serious burden on society. But research and development for drugs to treat these disorders has stagnated because of lack of demand, insufficient knowledge of pathophysiological mechanisms, and too few patients for clinical trials. In several countries--the United States, the EU, and Japan--specific legislation has been enacted to encourage pharmaceutical companies to expedite the development of drugs for rare diseases, orphan drugs, and to assure access to them. We analyze the strengths and weaknesses of the incentives in these laws and describe the status of rare diseases in China. We offer some recommendations for orphan drug legislation in China, based on local research on rare diseases.     

罕见病政策国际经验及对我国的启示

本研究系统梳理了近年来有关罕见病政策和服务的文献及文件,归纳了美国、日本、欧盟等国家和地区罕见病方面的立法及相关法规、管理制度、激励措施、保障政策等方面的政策设计和实践经验。目前,发达国家和地区对罕见病制定了较为系统的政策和法规,罕见病药品的研发和医疗保障等在法律层面得到了不同程度的保障。我国尚未形成针对罕见病的系统性的政策体系,结合中国实际,我国应从逐步建立系统的罕见病政策法规、拓宽筹资渠道、鼓励孤儿药研发,扩大新生儿筛查疾病的范围等方面着手,推动我国罕见病政策发展。     

An Evaluation Framework for Funding Drugs for Rare Diseases

ObjectivesFor rare diseases it may be difficult to generate data from randomized trials to support funding of a drug. Enzyme replacement therapies for diseases of inherited metabolic enzyme deficiency provide an example of this dilemma. The Ontario Public Drug Programs convened the Drugs for Rare Diseases Working Group to develop a policy for assessing these drugs.MethodsThe Drugs for Rare Diseases Working Group developed terms of reference expecting that the ideal policy product would be transparent and consistent and address unique aspects of the treatment of a specific rare condition while being adaptable to other dissimilar conditions. The perspective was that of a public payer addressing requests for funding generated for a specific drug, and included respect for the principles of “accountability for reasonableness” of Daniels and Sabin.ResultsA seven-step framework was developed and tested by using the case study of idursulfase for mucopolysaccharidosis II (Hunter disease). Estimation of clinical effectiveness was done by using decision modeling. The model developed informed funding recommendations and ultimately led to an agreement with the manufacturer allowing funding of idursulfase in Ontario.ConclusionsThis policy framework attempts to address the policy challenges of funding drugs for rare diseases. The framework will be used to assess other drugs in future and will inevitably require modification with experience. It is hoped that it may be of value to other policymakers.     

Socio-economic burden of rare diseases: A systematic review of cost of illness evidence

Cost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project (“Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe”) we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n = 29) and Haemophilia (n = 22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect.     

The needs of patients with rare disease in Serbia. Why do we need National Strategy for rare disease?

The patients with rare diseases in Serbia face the difficulties in procurement of medications as the Health insurance fund does not cover reimbursement for some medications, they face difficulties in receiving proper diagnosis which makes their position specific and complex. In an attempt to provide more support for the patients with rare diseases, their families and caregivers the helpline for rare diseases was established in October 2015. The aim of this research was to identify, examine and systematise needs of helpline users and forms of assistance provided by the team from the free helpline. The research was designed as a cross‐sectional study and was conducted between October 2015 and December 2016. The electronic database of National Organization for rare disease in Serbia helpline users was used as a data source. The user was the person who contacted helpline (patient, relative, friend, physician, etc). The “need” refers to the reasons for addressing the helpline. Helpline users had 549 needs in total; about healthcare—236 (42.98%), social care—113 (20.58%), psychological support—56 (10.20%) and other—144 (26.22%). Services were provided by the lawyer—130 (23.70%), social worker—71 (12.93%), Psychologist—56 (10.20%) and by all employees—292 (53.19%). The most common need for legal assistance among needs on healthcare was on legal aspects of access to and reimbursement of expenses for medications (32/74%–43.24%) and procedures for reimbursement of treatment abroad (11/74%–14.86%). The problems of patients with rare diseases and their families result primarily from the lack of relevant information and knowledge, as well as the non‐recognition of rare diseases in the laws and regulations of health and social care. Some problems can simply be solved by legal changes and by a better organisation and do not require additional funding. Only by adopting and implementing the National Strategy and Action Plan for Rare Diseases, the greatest number of problems and needs of people with rare diseases can be systematised and solved.     

European ordinance on orphan drugs: changes and threats

The Orphan Drugs Act has been officially implemented in all countries of the European Union since the year 2000. The Act aims to promote the development of treatments for rare diseases (prevalence < 5:10,000). Successful therapies for such diseases are granted market-monopoly for 10 years, during which no me-too products are allowed. There are problems concerning approval and reimbursement. Drugs already in use can also be registered as orphan drugs for a specific indication. In addition to this, European approval for the market authorization of new drugs does not automatically mean that the costs of the drug are reimbursed within the Netherlands, whereas that might well be the case in other EU countries. However, a faster procedure with respect to the reimbursement of drug costs in the Netherlands may not lead to the responsibilities for the carrying out of additional trials being transferred to those handling the treatment.     

The National Hospital Care Survey Is a Unique Source of Data on Rare Diseases

ObjectivesThis study aims to demonstrate the usefulness of the National Hospital Care Survey (NHCS) for studying rare diseases.MethodsNHCS contains data on millions of hospital patients from participating US hospitals, including diagnoses coded using 10th revision of International Classification of Diseases, Clinical Modification, making it likely that some of the patients have a diagnosed rare disease. The data for 2016 are unweighted and are not nationally representative. The Orphanet Nomenclature Pack lists 877 10th revision of the International Classification of Diseases codes that correspond to 536 rare diseases. Using Orphanet Nomenclature Pack, we identified NHCS patients with diagnosed rare diseases. We demonstrate the usefulness of NHCS for studying rare diseases by reporting, for each rare disease, the number of patients in NHCS with the disease, the average number of hospital encounters per patient, the average length of hospital stay, and the percent of patients who died either in-hospital or within 90 days after discharge.ResultsIn just 1 year of NHCS, we identified hundreds of rare diseases with ≥30 patients each (313 rare diseases in the inpatient setting and 273 in the emergency department setting). Although 10th revision of the International Classification of Diseases, Clinical Modification codes identify a small percent of known rare diseases, 12.9% of inpatient patients and 3.4% of emergency department patients had a diagnosed rare disease.ConclusionsNHCS is a rich source of administrative and electronic health record data on hospital patients with rare diseases, providing unique variables and observations on many patients. Although the percent of patients with each rare disease is low, a large percent of hospital patients has a rare disease.     

Epidemiology of obesity in Spain. Dietary guidelines and strategies for prevention

Obesity is considered a major Public Health issue in most developed countries nowadays for its wide spread across population groups, as well as its contribution to the development of chronic diseases, particularly cardiovascular diseases and diabetes. Available population data in Spain from the SEEDO'2000 study show a prevalence of obesity (BMI > or = 30 kg/m(2)) of 14,5% in adults aged 25-60 years, estimates based on individual measurement of body weight and height. Obesity rates are higher among women aged 45 years and older, low social class, living in semi-urban places. Geographical distribution of the problem shows a trend for higher rates towards the South- SouthEast of the country, i.e. Andalucía, Murcia and the Canary Islands. Population data for Spanish children and young people based on the enKid study--cross-sectional study on a random national sample of the population aged 2-24 years--estimate a prevalence of obesity of 13.9% for the whole group. Geographical distribution draws a similar pattern to that described for adults. Higher peaks of the problem are identified between 9-13 years among boys from a low socioeconomical background. The analysis of determinants of obesity in Spanish children and young people show that overweight and obesity is related to absence of breastfeeding, low consumption of fruit and vegetables; high consumption of cakes and buns, soft drinks and butchery products, low physical activity levels and a positive association with time spent watching TV. The joint consensus document produced by the Spanish Association of Pediatrics (AEP), Spanish Society of Community Nutrition (SENC) and Spanish Society for the Study of Obesity (SEEDO) considers a global strategy for the prevention of obesity from early stages in life. The important role of the family and the school setting as well as the responsibility of the Health Administration and Pediatric care in the prevention of obesity is highlighted in the document.     

Socioeconomic differences in the prevalence of common chronic diseases: an overview of eight European countries

BACKGROUND: Few studies have compared socioeconomic inequalities in the prevalence of both fatal and non-fatal diseases. This paper aims to give the first international overview for several common chronic diseases. METHODS: Micro-level data were pooled from non-standardized national health surveys conducted in eight European countries in the 1990s. Surveys ranged in size from 3700 to 41 200 participants. The prevalence of 17 chronic disease groups were analysed in relation to education. Standardized prevalence rates and age-adjusted odds ratios (ORs) were calculated. RESULTS: Most diseases showed higher prevalence among the lower education group. Stroke, diseases of the nervous system, diabetes, and arthritis displayed relatively large inequalities (OR > 1.50). No socioeconomic differences were evident for cancer, kidney diseases, and skin diseases. Allergy was more common in the higher education group. Relative socioeconomic differences were often smaller among the 60-79 age group as compared with the 25-59 age group. Cancer was more prevalent among the lower educated in the 25-59 age group, but among the higher educated in the 60-79 age group. For diabetes, hypertension, and heart disease, socioeconomic differences were larger among women as compared with men. Inequalities in heart disease were larger in northern European countries as compared with southern European countries. CONCLUSION: There are large variations between chronic diseases in the size and pattern of socioeconomic differences in their prevalence. The large inequalities that are found for some specific fatal diseases (e.g. stroke) and non-fatal diseases (e.g. arthritis) require special attention in equity-oriented research and policies.     

Selected gastrointestinal pathologies in tropical sub-Saharan Africa.

Doctors need to be well informed about differences in the presentation of certain diseases in tropical and temperate climates. In this article the characteristics of some gastrointestinal diseases, as they recur in sub-Saharan Africa, are briefly reviewed. Diseases of the stomach--including ulcertaion and cancer--are uncommon in Africa, although duodenal ulcer is common all over the tropics. In contrast, colorectal cancer is an extremely rare illness in sub-Saharan Africa, while hepatocellular carcinoma is much commoner than in Europe or North America and the very high incidence of this tumour in tropical countries is cause for concern.     

Förderung von Arzneimitteln für seltene Leiden durch die Europäische Gemeinschaft

The designation as an orphan medicinal product is required in order to benefit from European Union (EU) incentives for the development of drugs for rare diseases. The European Commission decides on the designation based on the opinion of the Committee for Orphan Medicinal Products within the European Medicines Agency. Designation as an orphan drug is clearly different from marketing authorization. Criteria for the designation as an orphan drug are the low prevalence of the disease (less than 5 in 10 000 inhabitants of the EU), severity of the disease and the expected significant benefit for the patients. Incentives include fee reductions and free scientific advice during development and up to ten years market exclusivity after marketing authorization. This article describes the procedure of orphan drug designation and highlights problems regarding coverage of treatment costs and increasingly individualized medicine.     

Epidemiology of osteoporosis

In many countries, including Croatia, there is no disease registry for osteoporosis and osteoporotic fractures. Epidemiological data show that the prevalence of osteoporosis is much higher in Asian people than in white European or North American populations, where the prevalence ranges between 10% and 15%. Epidemiological characteristics of osteoporosis in Croatia are similar to other European countries, though the incidence of osteoporotic fractures is somewhat higher. According to the annual report of registered diseases, the number of patients with osteoporosis and osteoporotic fractures increased during the last 10 years. In 2004, 0.70 % of all registered diseases in Croatia referred to osteoporosis and osteomalacia. The most important risk factors for osteoporosis are age, heredity, lifestyle, chronic diseases, hormonal abnormalities and physical characteristics of bone. Like in other chronic diseases, prevention measures are most important for disease control.