Tight control in the vascular endotype of systemic sclerosis.
Improving outcomes in pulmonary arterial hypertension associated with systemic sclerosis using personalized medicine, a predictive study.

Introduction
Systemic sclerosis (SSc) is a generalized auto-immune disease characterized by
inflammation, micro-vasculopathy and fibrosis, affecting skin and internal
organs. The primary cause of death in patients with SSc is interstitial lung
disease, followed by pulmonary arterial hypertension (PAH) (1). PAH has a
prevalence of 8-12% among SSc patients and is diagnosed by right heart
catheterization. The 3 year survival rate of PAH associated with SSc (PAH-SSc)
is estimated to be only 52%, despite the available targeted treatment (2).
Survival benefits when treated with targeted therapy are the greatest in those
diagnosed and treated in early stages of PAH (3). Screening programs, such as
the DETECT algorithm, consist of clinical parameters, echocardiography, lung
function with single-breath diffusion capacity for carbon monoxide (DLCO) and
N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, determined once a
year. However, the results of these assessments are by definition abnormal in
patients with PAH-SSc, and are therefore actual methods for diagnosing
established PAH and not for early stages of PAH or PAH yet to develop.
Therefore new diagnostic and prognostic biomarkers are needed to identify
patient subsets that are likely to develop PAH and to benefit most from
targeted therapy. If a high risk subset of patients is identified, personalized
screenings methods can be applied to reach earlier diagnosis of PAH. Then,
early treatment can be applied, and therewith improving the survival of this
complication of SSc would be feasible.

Recently, two functional antibodies are identified to predict the development
of PAH: anti-endothelin receptor type A (anti-ETaR) and anti-angiotensin II
receptor type I antibodies (anti-AT1R) (4). However, validation in a large,
prospective cohort is necessary for definitive proof of the value of these
vascular biomarkers. Several small cross sectional nail fold capillary
microscopic (NCM) studies showed that in PAH-SSc patients a significant
decrease in capillary density is present compared to SSc patients without PAH
and patients with idiopathic PAH (5, 6).

Hypothesis
We hypothesize that anti-endothelin receptor type A (anti-ETaR),
anti-angiotensin II receptor type I antibodies (anti-AT1R), and a reduction in
capillary density as seen with nailfold capillaroscopy (NCM) are biomarkers of
a 'vascular endotype of disease' and as a consequence, that in combination they
are predictive for the development of pulmonary arterial hypertension in
patients with SSc. The use of these *vascular endotype* biomarkers to select
SSc patients for more intensive PAH screening programs will allow more precise
and earlier identification of PAH patients, improving PAH-SSc related survival.

Specific objectives:
* To analyse the predictive value of the presence of anti-ETaR, anti-AT1R and a
reduction in capillary density, for the development of PAH in patients with
SSc, alone and in combination.
* To analyse whether anti-ETaR, anti-AT1R and a reduction in capillary density
have a predictive value over and above sex, age, and clinical variables as in
the DETECT algorithm.

Workplan
* A 3-year prospective, predictive study
* Patients with SSc fulfilling the ACR-EULAR classification criteria, with
DLCO< 80% predicted and without PH, aiming to find 50 incident cases
* Clinical evaluation, questionnaires laboratory assessments, nailfold
capillaroscopy en vascular receptor antibodies assessments every 3 months
* Pulmonary function tests and echocardiography every 6 months
* HRCT scan and/or right heart catheterization as clinical indicated following
current guidelines
* Primary endpoint: diagnosis of PAH by right heart catheterization
* Secondary endpoints: survival of PAH-SSc, development of digital ulcers as
symptom of vascular endotype of SSc, quality of life.

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