OT 1 - Prevention and treatment of digital ulcers

OT-Leaders: Marco MATUCCI-CERINIC (UNIFI), Francesco DELGADO (LEEDS)

Investigative objective

Background: The aetiology of DU is complex and multifactorial and the principal mechanisms underlying the DU formation are ischemic, mechanic and inflammatory, alone or in combination, on the basis of the SSc 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 [91].

An early therapy to prevent or rapidly heal DU is today considered a mandatory approach to maintain quality of life and spare the enormous costs due to conventional DU management.

Objectives:

(1)   Prevention: To identify the best treatment combination for prevention of DU, particularly in patients with very early SSc

(2)   Healing: To identify the best treatment associated with improved healing of DU

Primary endpoint(s)

• (1)   Prevention: Frequency of patients with new DU

  (2)   Healing: Time to healing of manifest DU

Secondary endpoint(s)

• (1)   Prevention: Time to development of new DU

  (2)    Healing: Frequency of patients with healed DU

Exploratory endpoints

To validate novel composite scores:

(1)   Prevention: A novel composite DU prediction score which will be tested against the already proposed capillaroscopic prediction score CSURI

Safety endpoints

Incidence of drug-related adverse events, incidence of withdrawal from treatment due to drug-related adverse events

Participants

Study population justification

The study population are adult and juvenile SSc patients from the EUSTAR cohort (MEDSonline database) and the jSScWG cohort.

For the assessment of DU prevention in patients with very early SSc, patients from the VEDOSS cohort and from the EUSTAR and jSScWG cohorts fulfilling the VEDOSS criteria (Raynaud’s phenomenon, puffy fingers, antinuclear antibodies (anti-topoisomerase I or anti-centromere antibodies), scleroderma-like pattern in nailfold capillaroscopy) as well as adult and juvenile systemic sclerosis patients with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria, respectively, will be investigated.

For the assessment of healing, only adult and juvenile systemic sclerosis patients with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria, respectively, will be investigated.

Inclusion criteria

1)       Prevention arm:

• Adult and juvenile systemic sclerosis patients, with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria, respectively, or patients with fulfilment of the preliminary criteria for very early diagnosis of systemic sclerosis (VEDOSS criteria), without and with history of DU (but currently without active DU*)
• Patients who are either currently on combination therapy of Bosentan and Sildenafil or received iv Iloprost at any time within the last 3 months or are receiving currently any other vasodilatation therapy (i.e. monotherapy with PDE5 inhibitors or endothelin receptor antagonists, as well as any treatment (combination or monotherapy) with ACE inhibitors and/or CCBs

2)       Patients Healing arm:

• Adult and juvenile systemic sclerosis patients, with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria, respectively, with currently ≥1 manifest DU*
• Patients who are either currently on combination therapy of Bosentan and Sildenafil or received iv Iloprost at any time within the last 3 months or are receiving currently any other vasodilatation therapy (i.e. monotherapy with PDE5 inhibitors or endothelin receptor antagonists, as well as any treatment (combination or monotherapy) with ACE inhibitors and/or CCBs

*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.

Trial design

Both the prevention and the healing studies are observational trials with 3 arms each

Treatment arms

Both the prevention and the healing study comprise the same 3 treatment arms

(1)   Patients receiving a combination of Bosentan and Sildenafil

(2)   Patients received i.v. iloprost at any time within the last 3 months

(3)   Patients receiving any other vasodilatation therapy (i.e. monotherapy with PDE5 inhibitors or endothelin receptor antagonists, as well as any treatment (combination or monotherapy) with ACE inhibitors and/or CCBs)

Patients without any vasodilatory treatment will not be observed.

Follow-up

Evaluations by the treating rheumatologists (clinical examination, capillaroscopy if necessary, Doppler if necessary, laboratory tests if necessary) will be performed at baseline and every 3 months thereafter during a planned 24-month follow-up