Executive Summary

In rare diseases, up to 90% of drug treatment is off-label, due to lack of adequate clinical research data. This is particularly true for the rare autoimmune rheumatic disease systemic sclerosis (SSc). Due to the severity of SSc, several immunomodulating drugs such as cyclophosphamide, methotrexate, azathioprine etc. are used off-label in this disease but their use is mostly based on case reports or small trials, which 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. The DeSScipher projects aimed at improving clinical practice in the management of SSc. The primary objective was to 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.

This approach is based on five observational trials (OTs), which were designed to analyse and evaluate current real-life treatment strategies for 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). Based on more than 2,000 prospectively enrolled and well-characterised people with SSc from SSc expert centres across Europe, the DeSScipher project aimed to compare the course of the disease under the different currently used off-label treatment regimens with respect to their efficacy and safety in the prevention or treatment of the organ manifestations under investigation. In addition, DeSScipher aimed to define and validate appropriate outcome measures. Achievement of these objectives was based on utilization of the unique pan-European EUSTAR network (EULAR Scleroderma Trials And Research group, established and operating under the auspices of the European League Against Rheumatism (EULAR)), which in total comprises more than 190 expert centres from all European countries. In cooperation with the juvenile SSc Working Group (jSSc-WG) of the Pediatric Rheumatology European Society (PRES), not only adult but also juvenile people with SSc were observed.

The DeSScipher project started in December 2012. After completion of preparative tasks (obtaining ethics approvals, training of staff at recruiting centres and set-up of the research database), enrolment of people with SSc into the five OTs commenced in April 2013. By the end of November 2015, a total of 2,433 individuals had been screened and 2,162 had been enrolled into at least one of the five OTs. As one person could simultaneously participate in multiple OTs, overall 4,686 datasets of people with SSc were followed prospectively in OT1-5 by the end of project month M36.

With the exception of the OT on hand arthritis, which can not be finalized as outlined below,, all DeSScipher partner and contributing EUSTAR centres have been prepared to and agreed to continue the follow-up of the remaining four OTs beyond the DeSScipher project period under the auspices of the EUSTAR network and World Scleroderma Foundation (WSF) up to November 2017 in order to facilitate the successful completion of the OTs. After completion of the OTs, the prospectively acquired data of the DeSScipher project will be merged with the retrospective data of the EUSTAR cohort to become the currently largest available clinical database of SSc worldwide.

After finalization of the follow-up period and data analysis of the four ongoing OTs, the DeSScipher project will not only be the largest multinational prospective observational research project ever performed in SSc but also become a template for how to manage such an approach including all predictable and unpredictable pitfalls prior to and during trials in rare diseases such as SSc. Its main achievement will be to provide scientific evidence for key clinical questions and problems and will facilitate to advance from off-label use of treatments to their official approval for everyday clinical use. Moreover, the findings of the DeSScipher OTs will contribute to the development of novel treatment recommendations to improve the management of SSc and its related morbidity and mortality.