CCL2 in the Circulation Predicts Long-Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts.

Abstract

There are few clinical predictors of the progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). The purpose of this study was to examine the predictive significance of key cytokines for long-term progression of ILD and survival in 2 independent cohorts of patients with early SSc. Plasma levels of 11 Th1/Th2 cytokines (interleukin-1β [IL-1β], IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor, CCL2, interferon-inducible T cell α chemoattractant, and interferon-γ-inducible 10-kd protein) were measured in 266 patients with early SSc in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) discovery cohort. Levels of CCL2, IL-10, and IL-6 were measured in 171 patients with early SSc in the Canadian Scleroderma Research Group (CSRG) replication cohort. The primary outcome measure was a decline in the forced vital capacity percent predicted (FVC%) value over time. A joint analysis of longitudinal FVC% values and survival was performed. After adjustment for age, sex, and ethnicity, CCL2 and IL-10 were found to be significant predictors of ILD progression in the discovery cohort. Higher CCL2 levels predicted a faster decline in FVC% values (b = -0.57, P = 0.032), while higher IL-10 levels predicted a slower decline (b = 0.26, P = 0.01). A higher CCL2 value was also predictive of poorer survival (hazard ratio 1.76, P = 0.030). In the CSRG replication cohort, higher CCL2 levels predicted a faster decline in FVC% values (b = -0.58, P = 0.038), but neither IL-10 nor IL-6 had predictive significance. A higher CCL2 level also predicted poorer survival (hazard ratio 3.89, P = 0.037). Higher CCL2 levels in the circulation were predictive of ILD progression and poorer survival in patients with early SSc, findings that support the notion that CCL2 has a role as a biomarker and potential therapeutic target.