Background/Purpose: The currently available clinical markers are not reliable predictors of long-term progression of systemic sclerosis (SSc) related interstitial lung disease (ILD). SSc patients have a distinct cytokine profile but the predictive significance of these cytokines for long-term progression of ILD has not investigated in early SSc cohorts. Herein, we examine the predictive significance of 11 key cytokines for progression of ILD and survival in a large early SSc cohort.

Methods: The plasma levels of 9 key Th1/Th2 cytokines (IL-6, MCP-1, TNF-α, IL-8, IL-5, IL-12, IL-10, IL13, and IL1β) and two interferon inducible chemokines (IP-10 and ITAC) were determined in the baseline samples of 266 SSc patients enrolled in the GENISOS cohort.  The primary outcome was decline in forced vital capacity (FVC% predicted) over time.  A total of 1016 FVC measurements fulfilled the American Thoracic Society criteria and were included in the analysis.  The mean follow-up time was 4.4 years. The predictive significance for long-term change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC% predicted) and survival data. This approach allows inclusion of all FVC measurements and accounts for dependency on survival. The primary cultured skin fibroblasts from SSc patients (n=10) and matched controls (n=10) were stimulated with MCP-1 for 24 and 48hrs and measured TGF- β1 protein levels by ELISA.

Results: Diffuse skin involvement was present in 156 patients (59%) and mean disease duration at enrollment was 2.5 years.  After adjustment for age, gender, and ethnicity, MCP-1 and IL-10 were significant predictors of ILD progression. MCP-1 predicted faster decline in FVC% predicted (b=-0.57, 95% CI: -1.11 – -0.04, p=0.032) while IL-10 predicted a slower decline in FVC% (b=0.26, 95% CI: 0.06-0.46, p=0.01) and had a protective effect. The predictive significance of MCP-1 and IL-10 did not change substantially in a multivariable that included both cytokines in addition to age, gender, and ethnicity (b=-0.64, p=0.014 and b=0.26, p=0.008, respectively)

The other investigated cytokines did not have independent predictive significance for ILD progression. Importantly, IL-6 did not predict faster decline in FVC% predicted (p=0.35).

Plasma MCP-1 was also predictive of poorer survival (HR: 1.93, 95% CI: 1.04 – 3.58, p= 0.032) while IL-10 did not predict survival.

MCP-1 and IL-10 levels were also determined in plasma from 97 age-, gender-, and ethnicity-matched unaffected controls.  Patients had higher MCP-1 and IL-10 levels than unaffected controls (p= 0.001and p=0.002, respectively).

In-vitro experiments with skin fibroblasts showed stimulation of TGF-β1 protein production with MCP-1 in patients and control fibroblasts, confirming the profibrotic effect of this cytokine.

Conclusion: MCP-1 is an important pro-fibrotic cytokine that predicts faster ILD progression and poorer survival in SSc while IL-10 predicts a slower ILD progression supporting the previously in-vitro studies indicating an anti-fibrotic effect of this cytokine. These findings can have important implications for drug and biomarker development in SSc related ILD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasma-mcp-1-and-il-10-levels-predict-long-term-progression-of-interstitial-lung-disease-in-patients-with-early-systemic-sclerosis/