Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19-CCL21 axis in patients with SSc-related PAH.
Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted.
CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39-10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12-10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001).
CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.