Antinuclear antibody (ANA) status predicts immune-related adverse events in liver cancer patients undergoing anti-PD-1 therapy

Abstract

Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA- group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients.

Keywords: PD-1; antinuclear antibody; common terminology criteria for adverse events; immune-related adverse event; primary liver cancer.

Graphical Abstract

Figure 1.

Frequencies of irAEs stratified by type (A) and grade (B) in ANA+ and ANA− patients with advanced liver cancer administered anti-PD-1 treatment. ANA, antinuclear antibody; anti-PD-1, anti-programmed death-1; irAE, immune-related adverse event

Figure 2.

Incidence rates of irAEs in ANA+ and ANA− patients with advanced liver cancer administered anti-PD-1 treatment. ANA, antinuclear antibody; anti-PD-1, anti-programmed death-1; irAE, immune-related adverse event. P-values were calculated by χ² test analysis

Figure 3.

ROC curve analysis of ANA status in the prediction of irAE occurrence. The area under the ROC curve (AUC) for ANA titers was 0.727. ROC, receiver operating characteristic; ANA, antinuclear antibody

Figure 4.

Incidence rates of irAEs after anti-PD-1 treatment in advanced liver cancer patients sub-divided according to ANA titers cutoff of 1:100, 1:320, and 1:1,000. (A) Rates of irAEs in patients with ANA titers ≥1:100, ≥1:320, and ≥1:1,000, respectively. (B) Rates of irAEs in patients with ANA titers <1:100, <1:320, and <1:1,000, respectively. ANA, antinuclear antibody; irAE, immune-related adverse event

Figure 5.

Time intervals between anti-PD-1 treatment and irAE onset. (A) Times from anti-PD-1 treatment to irAE onset in 34 patients with irAEs stratified by ANA status. (B) Median times from anti-PD-1 treatment to irAE onset in all advanced liver cancer patients sub-divided by ANA titer cut-offs of 1:100, 1:320, and 1:1,000, respectively. ANA, antinuclear antibody; anti-PD-1, anti-programmed death-1; irAE, immune-related adverse event. P-values were calculated by the log-rank test

Figure 6.

Kaplan–Meier survival curves in advanced liver cancer patients administered anti-PD-1 therapy. (A) PFS in ANA+ and ANA− patients. (B) OS in ANA+ and ANA− patients. ANA, antinuclear antibody; anti-PD-1, anti-programmed death-1; irAE, immune-related adverse event; PFS, progression-free survival; OS, overall survival. P-values were calculated by the log-rank test