OA28 CCL24 serum concentration predicts both vascular and fibrotic complications in systemic sclerosis: rationale for a biological target driven basket trial across disease subsets

Abstract

Abstract Background/Aims CCL24 is a novel target that was found to play a dual role in advancing pro-inflammatory and pro-fibrotic processes in systemic sclerosis (SSc). Previous studies reported that skin and serum CCL24 levels are elevated in SSc and that blocking of CCL24 was effective in preventing and attenuating experimental-induced fibrosis in murine models as well as interfering with endothelial cell activation. Here we tested the concentration of CCL24 in an observational cohort of patients with SSc and available clinical follow-up to determine its clinical value in predicting fibrotic and vascular complications of the disease. Methods Consecutive patients from a single-centre observational cohort were enrolled in this analysis. Clinical data were collected according to the EUSTAR minimal essential data set. Serum Concentration of CCL24 was measured by Luminex assay (Myriad RBM) and defined as “high” for patients over the upper quartile of the healthy control population (110 ng/ml). Interstitial lung disease (ILD) was defined by at least 10% parenchymal involvement at a high-resolution CT scan of the chest, while digital ulcer (DU) disease was defined by the presence of current or history of DU in the previous 6 months. Progressive fibrotic ILD was defined as previously described, according to Erice's criteria within 24 months. Clinical features were compared between CCL24 high vs low by Chi-Square and T-student tests. R software was employed for statistical analysis. Results 189 SSc patients (13% male) fulfilling 2013 ACR/EULAR classification criteria were enrolled in this study. Median (IQR) disease duration was 4 (IQR 2-10) years. 37 (27%) had diffuse cutaneous SSc, 60 (32%) had ILD, and 90 (48%) had DU disease. 52 patients (26%) were CCL24 High. These patients had a higher prevalence of DU (60%, p = 0.042), a higher median (IQR) mRSS [4(2-7) vs 2(0-5), p = 0.036) and showed a higher prevalence of ILD (42% vs 28%, p = 0.055); this was more significant among patients with limited cutaneous SSc (7% vs 12%, p = 0.037). Most importantly, among patients with PF-ILD (19/43 with available 24-month follow-up), 44% had significantly higher CCL24 serum concentration at baseline, compared to stable patients (1150 [817-1593] vs 725 [460-955]; p = 0.017). Consistent with these findings, in patients with ILD, having high CCL24 gave double the chance of progressing within 24 months (66% vs 32% of CCL24 low; p = 0.03). Conclusion We show here that within the context of an observational cohort of unselected patients, CCL24 serum concentration is associated with the presence of DU as well as worse skin and lung fibrotic involvement, suggesting that this molecule may be involved in both vascular and fibrotic manifestations of SSc. These results informed the rationale for a target-enriched basket randomized controlled trial to test the biological and clinical effect of CCL24 inhibition in SSc across cutaneous disease subsets. Disclosure E. De Lorenzis: None. A. Mor: None. R. Ross: None. S. Di Donato: None. R. Aricha: None. H. Levi: None. I. Vaknin: None. F. Del Galdo: Other; FDG received consultancies and research support from Abbvie, AstraZeneca, Boheringer-Ingelheim, Capella, Chemomab, Ergomed, Janssen, Kymab, Mitsubishi-Tanabe.