Background/Purpose:  Markers for early identification of progressive interstitial lung disease (ILD) in systemic sclerosis (SSc) are in demand. The proto-typical inflammatory chemokine CCL2 has been linked to lung fibrosis in SSc. Here, we aimed to: (i) To explore CCL2 in two independent SSc cohorts, including serum from a large and unselected SSc cohort and lung homogenates at time of lung transplant from patients with SSc-ILD. (ii) To assess associations between CCL2 in sera and lung fibrosis, lung function and survival. (iii) Determine cellular origin of CCL2 and its receptor CCR2 in lung tissue from SSc patients.

Methods:  Sera from the Oslo University Hospital (OUH) SSc cohort and healthy controls were analysed for CCL2 at baseline by enzyme immunoassay. High CCL2 (>0.66 ng/ml) was defined using mean value +2SD in control sera as cut-off. Paired clinical data, pulmonary function tests and the extent of fibrosis on HRCT images were obtained at baseline and follow-up. Lung tissue was collected at the time of lung transplantation from SSc and donor lungs at the UCLA. Concentrations of CCL2 in lung homogenates were determined by Luminex technology and expression of CCL2 and CCR2 in SSc tissue were assessed by immunohistochemistry (IHC).

Results:  CCL2 was elevated in sera from the OUH cohort (n=298) compared to healthy controls (n=100): 0.65 ng/ml (SD 0.80) versus 0.42 ng/ml (0.54), p=0.008. High serum CCL2 was identified in 79/298 SSc patients (27%). Extent of fibrosis, FVC% and DLCO% differed significantly between high and low CCL2 subsets (Table 1), as well as the total lung fibrosis progression rate (3.4% (SD 9.2) and 1.1% (SD 4.2, p=0.041). In multivariate analyses, CCL2 was associated with severe lung fibrosis >20% (OR 2.5, 95%CI 1.04-6.08, p=0.041), total fibrosis progression >5% (OR 2.7, 95%CI 1.14-6.19, p=0.024) and annual fibrosis progression >2.5% (OR 5.2, 95%CI 1.6-16.5), p=0.005). CCL2 was associated with increased mortality (HR 1.8 95%CI 1.02-3.27, p=0.043). Survival analyses showed that patients with high CCL2 had reduced 5- and 10-year cumulative survival compared to cases with low CCL2 (89% and 77%, compared to 95% and 88%, p=0.02). In the UCLA cohort, CCL2 was elevated in lung homogenates (n=12) compared to donor lungs (n=12) (0.61 ng/ml (SD 0.48) and 0.17 ng/ml (SD 0.23), p=0.007). IHC demonstrated a CCL2 co-localization with reactive type II pneumocytes, alveolar macrophages and infiltrating mononuclear cells. CCR2 was predominantly expressed on infiltrating mononuclear cells and on alveolar macrophages.

Conclusion: We have demonstrated an association between elevated levels of CCL2 and lung fibrosis progression, severe lung fibrosis and survival in SSc. Within the lungs, CCL2 is predominately co-localized with infiltrating mononuclear cells. The results reinforce the notion that high CCL2 may serve as a marker for progressive ILD in SSc and may potentially also represent a target for therapy in this disorder.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-level-of-chemokine-ccl2-is-associated-with-lung-fibrosis-progression-and-reduced-survival-in-two-independent-systemic-sclerosis-cohorts/