1. Define in detail how autoantibodies and changes in the B cell compartment correlate with different stages of clinical microvascular damage in SSc.2. Determine which soluble factors, including autoantibodies, in SSc-blood of clinically well-…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Insight in clinical associations and functional roles of functional vascular
autoantibodies in SSc. Identification of drugable targets that can interfere
with endothelial cell damage and development of fibrosis in SSC using
high-throughput in-vitro models with patient derived endothelial cells,
fibroblasts and blood samples.
Secondary outcome
Not applicable.
Background summary
Systemic sclerosis (SSc) is a severe disease characterized by the triad of
microangiopathy, dysregulated immune system and excessive fibrosis of skin and
internal organs. To date no curative treatment options with acceptable safety
profile are available. Immune dysregulation, characterized by presence of
specific autoantibodies, and microangiopathy, resulting in Raynaud*s
phenomenon, are among the earliest signs of the disease and predict further
progression. Recently, autoantibodies that bind to G protein-coupled receptors
including angiotensin II type 1 receptor (AT1R) and endothelin-1 type A
receptor (ETaR) that target receptors on endothelial cells, have been described
in SSc patients. Presence of these antibodies is associated with more severe
disease and increased chance of severe vascular complications.
We hypothesize that SSc sera itself contain the factors that cause endothelial
damage, and as such lead to vascular leakage, hypoxia and consequently tissue
fibrosis. We hypothesize that the factors that cause endothelial cell
dysfunction and damage are derived from dysregulated B cells and might
Study objective
1. Define in detail how autoantibodies and changes in the B cell compartment
correlate with different stages of clinical microvascular damage in SSc.
2. Determine which soluble factors, including autoantibodies, in SSc-blood of
clinically well-described SSc-patients contribute to endothelial damage in a
micro-vessel-on-chip model in vitro.
3. Identify, using the microvessel model and a functional model, targets that
can prevent endothelial cell damage
4. Characterize fibroblasts isolated from skin of patients with high risk for
severe fibrotic complications (*active profibrotic disease*) and evaluate
associations between clinical microvascular damage and proinflammatory
fibroblast markers.
Study design
Interventional, prospective, single center study
Intervention
skin biopsy of affected and non-affected skin of SSc patients.
Study burden and risks
No major risks are associated with this study. Skin biopsies are easily
mastered, quick and have a low incidence of infection, bleeding, non-healing or
significant scarring. No direct benefit from participation is expected for this
study. However, this project may deliver new drugable targets for SSc which is
a chronic and devastating disease for which currently no good treatment options
exist.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
Main inclusion criteria:
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. Diagnosis of systemic sclerosis according to ACR/ EULAR 2013 criteria or
very early diagnosis of systemic sclerosis based on presence of antinuclear
antibodies, and Raynaud*s phenomenon, and additionally presence of puffy
fingers OR abnormal nailfold capillaroscopy (thus not fulfilling ACR/ EULAR
2013 criteria
2. Age >= 18 years
3. Disease duration: a. equal to or less than 24 months since the first
non-Raynaud symptom, OR b. signs of active vasculopathy during the past 6
months including any one of the following: 1. new, painful pitting scars, 2.new
digital ulcer or peripheral necrosis, 3. Newly diagnosed pulmonary arterial
hypertension, 4. newly diagnosed scleroderma renal crisis.
4. Presence of Raynaud*s phenomenon
5. Signed informed consent
Additional inclusion criterium for skin biopsy:
1. Skin involvement proximal to the wrist or ankles
Exclusion criteria
Patients who have been treated with specific B cell depleting therapies (during
the past 12 months) or with autologous stem cell transplantation (ever) will be
excluded.
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL71598.058.19 |