A serum protein network early predicts the need for systemic immunomodulatory therapy in non-infectious uveitis

Abstract

Purpose

Early identification of patients with non-infectious requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associate proteomic clusters with the need for IMT during the course of their disease

Design

Multi-center cohort study.

Participants

This multi-center study was conducted in 230 treatment-free patients with active non-infectious uveitis.

Methods

We used aptamer-based proteomics (n=1,305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n=78) of patients and healthy controls, and validated our results independently in another Dutch cohort (n=111), and a U.S. cohort (n=67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use.

Main outcome measures

Serum protein levels, and use of IMT.

Results

Network-based analyses revealed a tightly co-expressed serum cluster (n=85 proteins) whose concentration was consistently low in healthy controls (n=26), but varied between patients with non-infectious uveitis (n=52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomical location of uveitis (hazard ratio (HR) [95%CI] = 3.42[1.22-9.5], P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation, r=0.57, P = 0.006). In an independent patient cohort (n=114), we defined robust IMT likelihood categories based on neutrophil measurements, confirming that patients with relatively high neutrophil count at diagnosis (>5.2×10⁹/L) had a significantly increased chance of requiring IMT during follow-up (HR [95%CI] = 3.2 [1.5-6.8], P = 0.002). The predictive power of the neutrophil proxy was further externally validated in a third cohort of 67 treatment-free US patients.

Conclusions

A serum protein signature correlating with neutrophil levels was highly predictive for IMT in human non-infectious uveitis. We developed an easy single and routinely available neutrophil-based clinical stratification tool that may serve as a novel objective blood biomarker to aid in clinical decision making for non-infectious uveitis.