Background/Purpose : Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles of chemokines CCL19/21 and their receptor CCR7 in lung inflammation leading to PAH. We aimed to assess the chemokine CCL19/21 axis in SSc-PAH.

Methods: Sera from two independent prospective SSc cohorts including Oslo University Hospital (OUH, n=298) and Lund University Hospital (LU, n=28), idiopathic PAH (n=12) and controls (n=100) were analysed for CCL19/CCL21 by ELISA. Levels were defined as high or low using [mean + 2SD] in controls as cut-off. Risk stratification at time of PAH diagnosis was performed according to 2016 European Society of Cardiology guidelines. PAH related events were defined as; (a) PAH progression (b) end-stage PAH (c) hospitalization for PAH worsening and (d) all-cause mortality.  Cellular sources of CCL21 and CCR7 within SSc-PAH lung tissue were determined by immunohistochemistry.

Results: CCL21 was higher in SSc than controls, and stable across time of PAH diagnosis. Clinical and demographics are shown in Table 1. 129/298 SSc patients underwent RHC at OUH, 41 were diagnosed with PAH and 25 with PH-ILD; at LU 16 patients had PAH. PAH was more frequent in patients with high CCL21 (>0.4 ng/ml) than low CCL21 (33.3% versus 5.3%, p<0.001) and higher than in PH-ILD and idiopathic PH (Figure 1). In multivariate analyses, CCL21 was associated with PAH (HR 5.1 95% CI 2.39-10.76, p<0.001) and predictive for new onset PAH (HR 3.3, 95% CI 1.52-7.10, p=0.003).  CCL21 was associated with occurrence of PAH related events (HR 4.7, 95%CI 2.12-10.46, p<0.001). Risk stratification at PAH diagnosis alone did not predict PAH related events, but when combined with CCL21 (HR 1.3, 95% C 1.03-1.60, p=0.027). Survival at 5- and 10-years differed between high and low CLL21 subsets (87% and 71% versus 96% and 91%, p<0.001). Main cellular sources of CCL21 in SSc-PAH lungs were vascular endothelial cells and circulating mononuclear cells (Figure 2), while CCR7 marked infiltrating vascular wall mononuclear cells.

Conclusion: CCL21 appears as a promising marker for SSc-PAH risk prediction and PAH progression. CCL21 may be part of a deregulated immune pathway linked to development of lung vascular damage in SSc.

Table 1:

Figure 1:

Figure 2: