Concept and objectives of DeSScipher

DeSScipher aims at improving clinical practice in the management of the rare autoimmune rheumatic disease systemic sclerosis (SSc) for which no orphan drug but only off-label treatments are available.

Over a three-year period, building upon the expertise of an established, large, multidisciplinary and experienced consortium combining physicians, biostatisticians and biologists with long-standing experience in the field of SSc, DeSScipher will provide a systemic, integrated approach to the disease. This approach will be based on observational trials, which will address different crucial dimensions of this systemic disease: (i) early detection/prevention and treatment, (ii) functional impairment and severe complications, (iii) affection of different organ systems (skin, joints, lungs and heart), (iv) juvenile and adult patients.

The project will compare the outcomes of different preventive measures and treatments with respect to efficacy and safety of currently used off-label drugs from the early to the advanced phases of the SSc-associated organ system involvements. For this purpose, DeSScipher will define and validate appropriate outcome measures. Based on the findings of DeSScipher, novel clinical guidelines will be developed and validated using a Delphi approach. In addition, by involving a broad community (the European umbrella group of patient associations from 18 countries, different stakeholders, multiple international recruitment centres and renowned experts in the field), these novel clinical guidelines will be disseminated rapidly and widely at the international level.

Achievement of these objectives will be possible through utilization of the unique pan-European EUSTAR group (Scleroderma Trials And Research group, established and operating under the auspices of the European League Against Rheumatism (EULAR)), which in total comprises more than 150 expert centres from all European countries and a network of paediatric rheumatologists. Within the established EUSTAR network, approximately 9,600 adult and 100 juvenile well-controlled and well-documented SSc patients are taken care of regularly and followed prospectively. In addition, the DeSScipher project will receive the momentum of the EUSTAR cohort, the largest SSc cohort worldwide, since the observational trials of DeSScipher can thus be based on a sufficiently large number of patients.

The DeSScipher project will also be perfectly in line with the objectives of the International Rare Disease Research Consortium (IRDiRC), the aims of which are to deliver 200 new therapies for rare diseases and diagnostic tools for the main entities within the 7,000 rare diseases by 2020. In addition, through a collaborative approach, DeSScipher will address the crucial challenges which have been identified by the IRDiRC for the purpose of reaching these aims by 2020:

(i) to establish and provide access to harmonized patient data and samples;

(ii) to perform the molecular and clinical characterisation of rare diseases;

(iii) to boost translational, preclinical and clinical research.

DeSScipher will also contribute to harmonizing policies related to research, standardisation of trials, and dissemination of results.

In rare diseases, up to ~90% drug use is off-label, due to lack of adequate clinical research data. This is particularly true for SSc. Due to the severity of this disease, several immunomodulating drugs such as cyclophosphamide, methotrexate, azathioprine etc. are used off-label in SSc but their use is mostly based on case reports or small trials, which - with the exception of the scleroderma lung study [5-7] - do not meet the usual standards of controlled clinical trials, as is frequently the problem in rare diseases. Thus, it has only been possible to establish preliminary guidelines for the management of SSc so far [8].

The DeSScipher project will provide scientific evidence for advancing from off-label use of treatments to their official approval for everyday clinical use. It will improve, as a consequence, the management of SSc in both adult and juvenile patients.

The concept of DeSScipher (see figure) is to use the EUSTAR long-term databank MEDSonline (Minimal Essential Data Set) and a novel diagnostic tool termed VEDOSS (Very Early Detection Of Systemic Sclerosis). The MEDsonline database follows patients with SSc who fulfil the American College of Rheumatology (ACR) classification criteria for SSc and has recruited approximately 9600 patients by the end of January 2012. In contrast, the VEDOSS subcohort of EUSTAR represents an inception cohort which prospectively follows adult patients who have an increased risk of developing SSc. At present, VEDOSS has recruited 610 patients. As soon as VEDOSS patients fulfil the classification criteria for SSc, they are transferred to MEDSonline. The unique MEDsonline and VEDOSS tools will be the basis for five observational trials (OT), which are designed to cover evolution phases of the disease from early functionally relevant manifestations such as digital ulcers (OT1) and hand arthritis (OT2) to the morbidity and mortality-driving manifestations such as interstitial lung disease (OT3), pulmonary hypertension (OT4) and severe heart disease (OT5). To this end, the EUSTAR cohort facilitates (i) the comparison of different treatment strategies in a significant number of well-characterised patients and (ii) the evaluation of the course of the disease under different therapeutic regimens with respect to their efficacy and safety in the prevention or the treatment of the organ manifestations under investigation.

The combined efforts of the well-connected EUSTAR network under the guidance of DeSScipher will provide a robust scientific basis for the development of novel clinical guidelines in SSc and will - together with the juvenile SSc Working Groups (jSScWG) of the Pediatric Rheumatology European Society (PRES) and the pan-European patient organisation FESCA - ensure their rapid dissemination and uptake for a better care of adult and juvenile patients afflicted by this severe disease. DeSScipher will also serve as a prototype approach for all other orphan diseases in the field of rheumatology and clinical immunology with similar problems in recruiting and documenting patients for testing novel drugs and establishing validated international guidelines.

The specific objectives of the DeSScipher project are:

·    To improve clinical practice in the management of SSc for both adult and juvenile patients

·    To facilitate an earlier detection and prevention of SSc and its organ manifestations and subsequently initiate disease- or organ-specific treatment

·    To improve both quality of life and morbidity/mortality in SSc by addressing functional impairments caused by digital ulcers and hand arthritis as well as life-threatening organ complications due to interstitial lung disease, pulmonary hypertension and severe heart disease

·    To develop and validate a reliable algorithm for detecting organ manifestations of SSc at an early stage in adult and juvenile patients at risk using novel tools such as the VEDOSS tool

·    To compare outcomes of prevention and treatment regimens in SSc to define appropriate outcome measures for SSc trials with an aim of defining at least 5 outcome measures at the end of the project in prevention and treatment

·    To evaluate the efficacy and safety of off-label treatments currently used to target the main disabling and life-threatening organ manifestations of SSc and thus define the safety and efficacy based on specific endpoints at the end of the project

·    To contribute actively to the development and rapid dissemination of national, European and international guidelines for the diagnosis and management of adult and juvenile SSc using the EUSTAR and PRES international network with an aim of disseminating to at least all European countries involved in the project and to five other countries based on the patients involved in the patient association FESCA at the end of the project.