Assessing the role of local inflammatory, fibroproliferative, and osteogenic biomarkers in Systemic Sclerosis related Interstitial Lung Disease.

Systemic sclerosis (SSc) is a rare progressive autoimmune disease hallmarked by
severe vasculopathy, leading to skin and internal organ complications and
premature mortality. A considerable proportion of SSc patients develop Systemic
Sclerosis related Interstitial Lung Disease (SSc-ILD), for which treatment
options are limited. Although extensive SSc-ILD has been shown to be associated
with large fibroproliferative changes, early phases of limited SSc-ILD seem to
be characterized by local inflammation. Pre-clinical and early clinical studies
indicate that interleukin-6 may play a central role during the early phase of
SSc-ILD. Additionally, patients with SSc are prone to enhanced calcification of
skin (calcinosis cutis) and vasculature. This calcification process is
strongly associated with local inflammation in the skin, which is a process
that may very well also occur in internal organs and serve as an early proxy
for long-term SSc-related complications. In fact, in patients with SSc, diffuse
pulmonary ossifications are frequently observed, which may indicate a common
pathway of systemic inflammation, fibrosis, and calcification in interstitial
lung disease (ILD) in SSc.

Hypothesis: Assessment of the proinflammatory, profibrotic and osteogenic
profile of the lungs in patients with SSc could serve as early markers of
disease, and could potentially facilitate upfront treatment in patients with
limited SSc-ILD.

1. To compare the proinflammatory, profibrotic and osteogenic cytokine profile
in BAL fluid between SSc patients without ILD, with limited ILD, and with
extensive ILD.
2. To compare the proinflammatory, profibrotic and osteogenic differentiation
of fibroblasts isolated from lung BAL fluid and lung biopsies between SSc
patients without ILD, with limited ILD, and with extensive ILD.
3. To compare the expression of markers involved in the calcification process
in lung biopsies assessed by immunohistochemistry between SSc patients without
ILD, with limited ILD, and with extensive ILD.
4. To assess the association of diffuse pulmonary ossifications on HRCT with
the cytokine profile in BAL fluid, the fibroblast differentiation in lung
fibroblasts, and calcification process in lung tissue in patients with SSc

This is an explorative substudy of the CALC-SSc study (NL65651.042.18, METC
2018.373), with a case-control and prospective longitudinal design.

Attempts will be made to have patients and healthy controls visit our center
only once for assessment of all study parameters. Blood drawing will be
combined with routine clinical practice assessments to minimize the
venipuncture burden. Bronchoscopy may result in minor discomfort (not needing
medical attention) in <10%, and in <1% it may result in more severe
complications (pneumonia and bleeding) needing medical attention and
intervention. By excluding participants using anticoagulants or anti-platelet
drugs, the risk of bleeding is limited as much as possible.