Prevention and Treatment of Digital Ulcers in Systemic Sclerosis

Study Overview
=================
Brief Summary
-----------------
Systemic sclerosis is an orphan, multiorgan disease affecting the connective tissue of the skin and several internal organs. Digital ulcers are frequent and have a major impact on the quality of life in patients with systemic sclerosis. The etiology of digital ulcers is complex and multifactorial and the principal mechanisms underlying the digital ulcers formation are ischemic, mechanic and inflammatory, alone or in combination, on the basis of the systemic sclerosis vasculopathy. Consequently, there are at least three types of DU: (i) those localized at the tips of the fingers and toes, mainly resulting from an ischemic process, (ii) those localized on the dorsal aspect of the fingers where the skin retraction due to fibrosis over bony prominences seems to be the main cause, and (iii) those evolving on a pitting scar or subcutaneous calcinosis due to a combined irritative-inflammatory mechanism. An early therapy to prevent or rapidly heal digital ulcers is today considered a mandatory approach to maintain quality of life and spare the enormous costs due to conventional digital ulcer management. This observational trial is part of the collaborative project DeSScipher, one out of five observational trials to decipher the optimal management of systemic sclerosis. Aim of this observational trial is: To identify the best treatment combination for prevention of digital ulcers in patients with fulfilment of the new ACR/EULAR SSc criteria or the preliminary VEDOSS criteria for very early diagnosis of systemic sclerosis To identify the best treatment associated with improved healing of digital ulcers in patients with fulfilment of the new ACR/EULAR SSc criteria Thus, the observational trial consist of a prevention arm and a healing arm.

Conditions
-----------------
Systemic Sclerosis, Ulcer

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Juvenile and adult patients with diagnosis of systemic sclerosis according to the ACR/EULAR SSc criteria or the PRES/ACR/EULAR juvenile SSc criteria for enrollment into the prevention and healing arm Patients with fulfilment of the preliminary criteria for very eary diagnosis of systemic sclerosis (VEDOSS criteria) for enrollment into the prevention arm Patients with active digital ulcers will be allocated into the healing arm. Patients without previous or history of digital ulcers (but currently without active digital ulcers) will be allocated into the prevention arm. Definition of digital ulcers (DU): DU are 1) loss of tissue, 2) DU derived from digital pitting scars and 3) DU derived from calcinosis. IN THIS STUDY WE CONSIDER ONLY DU (1) LOSS OF TISSUE. THE OTHER DU (2) and DU (3) ARE REGISTERED IN THE DATA BASE IF THEY ARE PRESENT, BUT ARE EXCLUDED FROM EVALUATION.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Prevention arm: CCB & i.v. iloprost<br>prevention arm: patients receiving a combination of calcium channel blockers (CCB) and concomitant i.v. iloprost (i.v. iloprost at least in the last three months) | |
| Prevention arm: bosentan & sildenafil<br>prevention arm: patients receiving a combination of the endothelin receptor antagonist bosentan and the Phosphodiesterase-5 inhibitor sildenafil | |
| Healing arm: CCB & i.v. iloprost<br>healing arm: patients receiving a combination of calcium channel blockers (CCB) and concomitant i.v. iloprost (i.v. iloprost at least in the last three months) | |
| Healing arm: bosentan & sildenafil<br>healing arm: patients receiving a combination of the endothelin receptor antagonist bosentan and the Phosphodiesterase-5 inhibitor sildenafil | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention arm: Number of new digital ulcers |  | 24 months | 
| Healing arm: Time to healing of manifest digital ulcers |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention arm: Time to development of new digital ulcers |  | 24 months | 
| Healing arm: Number of healed digital ulcers |  | 24 months |