Epidermolysis bullosa House Austria and Epidermolysis bullosa clinical network

According to Regulation (EC) N. 141/2000 of the European Parliament and of the Council, rare or orphan diseases (RD) are defined by a prevalence of 1 out of 2000 or less [1]. The vast majority of RD (i. e. 80%) have a genetic origin, while (auto) immunological, oncological and toxicological causes are found in only 10%, 4% and 3%, respectively (plus 3% others) [2]. The disease burden by RD is often considerable. Patients suffer from a chronic and often debilitating, progressive disease course with significant morbidity or even mortality. Treatment is mostly symptomatic. With respect to diagnostics, clinical parameters alone can be misleading and their interpretation challenging because (prototypic) findings, if appearing at all can be transient, inconsistent or not obvious in early infancy, when an accurate diagnosis is most critical. These limitations are further aggravated by the lack of standardized clinical data due to the rarity of RD and also by a marked genotypic variability of mutation-based disorders. These features of RD account for the occurrence of misdiagnoses and non-diagnoses, resulting in additional impairment and inadequate care, despite the fact that some RD are compatible (also by the use of orphan drugs) with a normal life if diagnosed on time. Socioeconomically, RD may not only significantly compromise educational and professional opportunities as well as social life but also cause enormously high costs, because treatment and management strategies are often very expensive and life-long. Moreover, cost-intensive regular follow-up and thorough examinations of RD patients are usually necessary in those mostly multisystem disorders. The limited access to clinical expertise and experience in diagnostic, therapeutic, organizational, bureaucratic, financial and research terms is mainly due to the small, seemingly negligible size of the respective patient cohort in each country, a major burden that makes RD often “the poor cousin” of public health policy, pharmaceutical industry and research funding.

The key specificities of RD, including great heterogeneity, limited number of patients, scarcity of relevant knowledge and expertise as well as enormous costs predispose them as a unique target for a very high added value of cooperative action at national and international levels. This has been repeatedly acknowledged by the EU, e. g. by the Orphan Medicinal Product Regulation to set up criteria for orphan designation in the EU and to describe the incentives (e. g. 10-year market exclusivity, protocol assistance and access to the centralized procedure for marketing authorization) to encourage research, development and marketing of medicines to treat, prevent or diagnose RD [1]. The issue of RD was furthermore addressed by the Commission Communication 697 in 2008 [3] and the subsequent Council Recommendation on an action in the field of rare diseases in 2009 [4]. The main objective of these activities is to improve the access and equity to efficient prevention, diagnosis, treatment, care and research for patients suffering from a RD throughout the European Union (EU). This includes an overall community strategy to support member states to integrate national actions and initiatives into comprehensive intersectoral national action plans/strategies as well as transnational reference networks for RD, thereby gathering national expertise on RD and pooling it together with European counterparts (Table 1). In Austria, the national action plan for RD was recently approved by the Federal Ministry of Health [5].

An inventory of the initiatives, plans and strategies undertaken in the EU member states has been jointly produced by the EU Committee of Experts on Rare Diseases (EUCERD, www.​eucerd.​eu) and EUROPLAN (www.​europlanproject.​eu), aiming to promote the implementation of the EU recommendation on rare diseases in the EU member states [6]. Core indicators to monitor national plans or strategies on RD of the member states have been recently published [7] and are instrumental for the decision-making process related to the adoption, assessment and further development of public policies for RD (Table 1).

Implementation of centres of expertise (CE) at the national level and their supranational integration into European reference networks (ERN) at the EU level has been defined as a key element of a coordinated European RD strategy by the European Commission High Level Group on health services and medical care that brings together experts from all member states to work on practical aspects of collaboration between national health systems in the EU [8, 9].

The CE provide expert structures for the diagnosis, management and care of RD patients at highest standards in defined catchment areas (Table 2; [8]). They bring together and coordinate multidisciplinary skills to serve the medical, rehabilitation and palliative needs of RD patients with, as far as applicable, evidence of good outcomes (including national and European legal provisions, participation in internal and external quality schemes) and also in close collaboration with patient organizations and alliances, such as the European Organization for Rare Diseases (EURORDIS, www.​eurordis.​org) to bring in their perspective. Their high level of expertise and experience is documented, for instance, by the annual number of referrals and second opinions, and through peer-reviewed publications, grants, positions, teaching and training activities. The CE further provide specialized laboratories or other core facilities, demonstrate a strong contribution to research, connect with each other and patient groups, appropriate health and social care providers, relevant research groups and diagnostic laboratories at national and international level, educate and train healthcare professionals as well as elaborate and disseminate good practice guidelines and disease information.

At the continental level European reference networks (ERN) should provide a framework for healthcare pathways for patients with RD at a high level of integrated expertise, e.g. EUCERD recommendations on rare disease European reference networks (RD ERNS) [9]. Within ERN, CE are the core nodes. The network structures comprise a horizontal (CE at the same level, such as expert centres across different member states), vertical (different points of care of a healthcare pathway from primary care through to the CE providing expertise) and diagonal dimension (when different specialities such as social, rehabilitative and psychological specialists, physiotherapists and other services work together). The EU public health program 2020/2025 gives priority to RD ERN aiming at the introduction of 20–30 RD ERN until then.

On the background of the cross-border healthcare directive, which commonly along a national preauthorization procedure, allows accessibility of CE to all patients with conditions requiring a particular concentration of expertise or resources in medical disciplines that is not available in their home member state [11]. Key strategic elements of ERN include a defined governance, oversight structures, clear and comparable methods for evaluation and strong leadership qualities of co-ordinating site(s) to provide optimal cross-border services to all EU citizens (Table 3; [9, 12, 13]). The ERN should thereby provide access to the highest level of expertise, facilitate collaborative disease management and data collection for clinical research to, e. g. cope with recruitment issues, maximize the cost-effective use of European resources by concentrating them where appropriate and exploit innovations in medical science as well as health technologies (ERARE project for the improvement of RD research infrastructures; www.​erare.​eu).

Relevant cost factors for ERN include project management, data collection and co-ordination in registries, information technology (IT), website and communication platforms, support for network meetings (within and between ERN), training and education packages (online, face to face), board activities as well as evaluation measures [9]. In this respect, the financial support from EU authorities is assumed to be proportional to the number of targeted patients, number of centres integrated as well as the number of diseases covered in terms of information to be produced and disseminated [9].

EB-CLINET (www.​eb-clinet.​org) is a clinical network of EB centres and experts with currently 68 European and international partners in 52 countries worldwide. By linking clinical expertise in EB, the purpose of EB-CLINET is to share supranational competence and knowledge, to strengthen clinical cooperation, and to provide a basis for clinical trials. As an international collaboration, it operates on:

Ultimately, EB families, wherever they live, should be able to receive professional high-quality support involving fair and dignified access to care services without the need for exhausting travel, language barriers or financial obstacles. The EB-CLINET has organized two international meetings in Salzburg, Austria, with over 90 delegates from 29 different countries around the world. The 4th EB-CLINET conference will take place in Salzburg in September 2017.

The exponential advances in molecular biology made over the last two decades have elucidated the etiology of many of the RD. As a consequence, research on these diseases has ultimately proved to be very useful for a better understanding of the mechanism of very common conditions, as they may represent a model of dysfunction of a distinct biological pathway. These findings paved the way for a new era of targeted therapeutic interference, in dermatological terms to mention icatibant for hereditary and sporadic angioedema, vismodegib for basal cell carcinoma and Gorlin syndrome, as well as diacerein for EB [14‐16].

Facing the challenging characteristics of RD and current limitations in care and support of patients with RD as outlined and likewise the promising perspectives (in research and therapy) and commitments by national and supranational healthcare authorities, the medical community should actively participate in the establishment and support of institutions of expertise for diagnosis, treatment and care of RD committed to the principles of reference in medical assistance, academics and research. In this spirit, the initiative of a reference network for genodermatoses (GERN) was launched at the 22nd Congress of the European Academy of Dermatology and Venereology (EADV) in 2013 in Istanbul. This networking activity was originally driven by the sole initiative of 25 participating experts from 13 countries and from 2 European and International patient networks and formally independent of the official application, assessment and approval procedures established by the European Commission for ERN that are currently ongoing.

Participants have proposed and discussed strategies to meet the three designated core components of GERN: disease registries, good clinical practice guidelines and best standards of diagnosis and care as well as training and education tools. Intended as a cluster of excellence, it should be built on pre-existing networks, such as the Fondation René Touraine (www.​fondation-r-touraine.​org), Geneskin (http://​cordis.​europa.​eu/​result/​rcn/​51882_​en.​html), EB-CLINET (www.​eb-clinet.​org) and the European Network for Ichthyosis e. V. (www.​ichthyose.​eu). The GERN is coordinated by the Fondation René Touraine Genodermatoses Network Committee in close collaboration with the EADV Genodermatoses Task Force Coordinators. GERN, currently involving 56 partners, also participated in the first call for applicants to provide a proposal for the establishment of (officially designated) ERN that was launched by the European Commission in Spring 2016 (http://​ec.​europa.​eu/​health/​ern/​policy/​index_​en.​htm). The first ERN are expected to be formally approved and operational in Spring 2017.

Multidisciplinary care based on recommendations and decisions made at expert round tables and committed to the principles of quality assurance at CE will allow early and accurate care for patients in their proximity. Likewise, local healthcare providers will benefit from the reputation reflected by the efforts of such coordination centres for RD as well as from the cost-efficiency due to non-redundant but comprehensive and multidisciplinary diagnostics, focused assessment strategies and optimized treatment protocols. Concentrating and strengthening these efforts with respect to RD in collaborating reference networks will also facilitate governmental and private funding in times of progressively limited financial resources. Acquisition of research grants and international programs fostering research will stimulate the academic status of participating institutions. Overall, these intentions will have a major impact on scientific, medical, social and health-economic issues, raise public awareness, understanding and support and also improve the medical supply in the general population across Europe.