Prognostic and predictive markers of systemic sclerosis-associated interstitial lung disease in a clinical trial and long-term observational cohort

Abstract

Objectives: To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART).

Methods: The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses.

Results: In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P < 0.001) and 0.6% faster yearly decline (P = 0.03) than females.

Conclusion: Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab.

Trial registration: ClinicalTrials.gov: NCT02453256.

Keywords: Autoantigens and autoantibodies; biological therapies; biomarkers; cytokines and inflammatory mediators; interstitial lung disease; scleroderma and related disorders; systemic sclerosis.

Graphical abstract

Figure 1.

FocuSSced placebo arm prognostic factors. Data are shown as time to ≥10% ppFVC decline according to disease duration (A), sex (B), anti-topoisomerase 1 antibodies (C), and age (D) in the focuSSced placebo arm only. ppFVC: percent-predicted forced vital capacity

Figure 2.

SMART—time to development of threshold FVC levels. FVC: forced vital capacity

Figure 3.

Performance of biomarkers as prognostic factors in the focuSSced tocilizumab arm. Data are shown for patients in the focuSSced tocilizumab arm only: IL-6 (A), IL-6R (B), platelets (C), and CRP (D). FVC: forced vital capacity; IL-6R: IL-6 receptor; ppFVC: percent-predicted FVC