High-titer antinuclear antibodies are associated with severe immune-related toxicity and exploratory survival outcomes in advanced gastric cancer immunotherapy.

BACKGROUND

Clinicians often screen for autoantibodies before initiating immune checkpoint inhibitors (ICIs) in advanced gastric cancer (GC), yet the utility of organ-specific panels remains unclear.

OBJECTIVES

To evaluate the association of baseline antinuclear antibody (ANA) titers and organ-specific autoantibodies with severe immune-related adverse events (irAEs) and clinical outcomes in patients with advanced GC receiving ICIs.

DESIGN

Single-center retrospective cohort study.

METHODS

We retrospectively analyzed 244 patients with advanced GC treated with ICIs. Baseline ANA titers and organ-specific antibodies, including Ro52, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb), were systematically evaluated. Associations with grade 3-4 irAEs were assessed using Firth's penalized logistic regression. Progression-free survival (PFS) was analyzed using Kaplan-Meier methods, Cox proportional hazards regression, subgroup analyses, and propensity score matching.

RESULTS

The prevalence of organ-specific antibodies was low (<7%) and failed to predict toxicity. In contrast, high-titer ANA (≥1:160, 17.6% of patients) predicted grade 3-4 irAEs (OR = 7.98, 95% CI: 3.35-19.5; p < 0.001). Although the high-titer ANA group included a numerically higher proportion of PD-L1-negative tumors, exploratory survival analyses showed longer PFS in patients with high-titer ANA in univariable analysis (p = 0.038), whereas the association was attenuated after multivariable adjustment (adjusted HR = 0.60, 95% CI: 0.35-1.01, p = 0.056) and remained borderline after propensity score matching (p = 0.049).

CONCLUSIONS

High-titer ANA was associated with an increased risk of severe irAEs in patients with advanced GC receiving ICIs. Its association with longer PFS was exploratory and requires prospective validation. These findings suggest that ANA titers may help baseline toxicity risk stratification, whereas routine screening for low-yield organ-specific autoantibodies may offer limited clinical utility in unselected patients.