Prevention and Treatment of Digital Ulcers in Systemic Sclerosis

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:

1. 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
2. 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.

Study Overview

• Status: Unknown
• Conditions: Ulcer; Systemic Sclerosis

• Study Type: Observational
• Enrollment (Anticipated): 420

Contacts and Locations

• Study Contact: Name: Marco Matucci-Cerinic, Prof.; Email: marco.matuccicerinic@unifi.it
• Study Contact Backup: Name: Francesco Del Galdo, Prof.; Email: F.DelGaldo@leeds.ac.uk

Study Locations

• France
  • Paris, France, 75014
    • Recruiting
    • Université Paris Descartes, Hôpital Cochin, Service de Rhumatologie A & INSERM 1016
    • Principal Investigator: Yannick Allanore, Prof.
• Germany
  • Bad Nauheim, Germany, 61231
    • Recruiting
    • Justus-Liebig-University Gießen, Kerckhoff Clinic, Departement of Rheumatology and Clinical Immunology
    • Principal Investigator: Ulf Müller-Ladner, Prof.
    • Sub-Investigator: Marc Frerix, Dr.
    • Sub-Investigator: Ingo H. T, Dr.
  • Berlin, Germany, 10117
    • Recruiting
    • Charité Universitätsmedizin Berlin, Charité Centrum 12 für Innere Medizin und Dermatologie, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie
    • Principal Investigator: Gabriela Riemekasten, Prof.
  • Hamburg, Germany, 22081
    • Recruiting
    • Centre for Pediatric Rheumatology, Klinikum Eilbek
    • Principal Investigator: Ivan Foeldvari, Dr.
• Hungary
  • Pecs, Hungary, H-7622
    • Recruiting
    • Pecsi Tudomanyegyetem - University of Pecs
    • Principal Investigator: Laszlo Czirjak, Prof.
• Italy
  • Firenze, Italy, 50139
    • Recruiting
    • University of Florence, Denothe Centre, Division of Rheumatology AOUC, Department of Biomedicine
    • Principal Investigator: Marco Matucci-Cerinic, Prof.
  • Napoli-Italia, Italy, 5-80131
    • Recruiting
    • Policlinico, Via Pansini
    • Principal Investigator: Gabriele Valentini, Prof.
• Switzerland
  • Basel, Switzerland, CH 4012
    • Recruiting
    • Felix-Platter Spital, University of Basel
    • Principal Investigator: Ulrich Walker, Prof.
  • Zurich, Switzerland, 8006
    • Recruiting
    • University of Zurich, Department of Rheumatology
    • Principal Investigator: Oliver Distler, Prof.
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Recruiting
    • The Universitiy of Leeds, Division of Rheumatic and Musculoskeletal Disease, St James's University Hospital
    • Principal Investigator: Francesco Del Galdo, Dr.
  • London, United Kingdom, NW3 2QG
    • Recruiting
    • Royal Free Hospital, University College London
    • Principal Investigator: Christopher Denton, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The study population are adult and juvenile systemic sclerosis patients from the EUSTAR cohort (MEDSonline database), the VEDOSS cohort and the jSScWG cohort

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Prevention arm: CCB & i.v. iloprost; 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; prevention arm: patients receiving a combination of the endothelin receptor antagonist bosentan and the Phosphodiesterase-5 inhibitor sildenafil
Healing arm: CCB & i.v. iloprost; 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; 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	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	Time Frame
Prevention arm: Time to development of new digital ulcers	24 months
Healing arm: Number of healed digital ulcers	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevention arm: novel composite digital ulcer prediction score	Prevention: A novel composite digital ulcers prediction score which will be tested against the already proposed capillaroscopic prediction score CSURI	24 months
Healing arm: novel composite outcome score for the assessment of worsening of digital ulcers despite treatment	Healing: A novel composite outcome score for the assessment of worsening of digital ulcers despite treatment	24 months

Collaborators and Investigators

• Sponsor: marco matucci cerinic
• Collaborators: University of Pecs; Charite University, Berlin, Germany; University of Zurich; University College, London; University of Leeds; University of Campania "Luigi Vanvitelli"; University of Basel; University of Giessen; European Union; University of Paris 5 - Rene Descartes; Schoen Klinik Hamburg Eilbek
• Investigators: Study Chair: Ulf Müller-Ladner, Prof., Justus-Liebig-University Gießen, Kerckhoff Clinic, Departement of Rheumatology and Clinical Immunology; Principal Investigator: Marco Matucci-Cerinic, Prof., University of Florence, Denothe Centre, Division of Rheumatology AOUC, Department of Biomedicine; Principal Investigator: Francesco Del Galdo, Dr., The Universitiy of Leeds, Division of Rheumatic and Musculoskeletal Disease, St James's University Hospital

Publications and helpful links

General Publications

• Blagojevic J, Bellando-Randone S, Abignano G, Avouac J, Cometi L, Czirjak L, Denton CP, Distler O, Frerix M, Guiducci S, Huscher D, Jaeger VK, Lorand V, Maurer B, Nihtyanova S, Riemekasten G, Siegert E, Tarner IH, Vettori S, Walker UA, Allanore Y, Muller-Ladner U, Del Galdo F, Matucci-Cerinic M; EUSTAR co-workers. Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey. Arthritis Res Ther. 2019 Jan 24;21(1):35. doi: 10.1186/s13075-019-1822-1.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Anticipated): June 1, 2017
• Study Completion (Anticipated): June 1, 2017

Study Registration Dates

• First Submitted: April 16, 2013
• First Submitted That Met QC Criteria: April 16, 2013
• First Posted (Estimate): April 19, 2013

Study Record Updates

• Last Update Posted (Estimate): April 25, 2013
• Last Update Submitted That Met QC Criteria: April 24, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse
• Other Study ID Numbers: HEALTH-F5-2012-305495-OT1