ABSTRACT:

Background/Purpose: The currently available clinical markers are not reliable predictors of long-term progression of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). In a previous study conducted in the GENISOS (Genes versus Environment in Scleroderma Outcome Study) cohort, none of the baseline clinical variables (including serology and disease type) was predictive of long-term decline in forced vital capacity (FVC). Elevated C-reactive protein (CRP) levels have been reported in a subset of patients with SSc and correlated with disease severity as well as shorter survival. Herein, we examine the predictive significance of CRP for progression of ILD (based on longitudinally obtained serial FVC) and survival in a large early SSc cohort.    Methods: We compared the plasma CRP levels in 266 SSc patients enrolled in the GENISOS cohort (mean disease duration at enrollment 2.5 years, 59% diffuse cutaneous involvement) to that of 97 age, gender and ethnicity-matched controls. Subsequently, the correlation between the plasma CRP levels and concomitantly obtained markers of disease severity was assessed. The primary outcome was decline in FVC over time. A total of 1,016 FVC measurements fulfilled the American Thoracic Society/European Respiratory 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 % predicted FVC) and survival data. This approach allows inclusion of all FVC measurements and accounts it for survival dependency.  Results: We confirmed that the baseline plasma CRP levels were significantly higher in SSc patients than matched controls (p=0.027). In addition to body mass index and age at baseline, the plasma CRP levels were associated with absence of anti-centromere antibodies (p=0.043). Also consistent with previous reports, plasma CRP levels correlated with the concomitantly obtained joint, skin and lung components of the Medsger Severity Index, as well as, FVC, DLco, mRSS. More importantly, baseline CRP levels correlated with shorter survival (p<0.001) and predicted the long-term decline in % predicted FVC (β= -0.35, 95% CI: -0.61 - -0.09, p= 0.006).  The predictive significance of CRP for ILD progression was independent of potential confounders (age at baseline, gender, ethnicity, body mass index, and treatment with immunosuppressive agents) in the multivariable model (β= -0.37, 95% CI: -0.63 – -0.11, p=0.005).

Conclusion: In the present study, we show for the first time that the baseline CRP levels are predictive of long-term ILD progression. High CRP levels can identify the subgroup of patients that would benefit from more intensive monitoring and treatment.