Predictive value of pre-existing thyroid autoantibodies for PD-1 inhibitor-induced hypothyroidism: a retrospective cohort study.

INTRODUCTION

Immune checkpoint inhibitors (ICIs), particularly programmed cell death-1 (PD-1) inhibitors, have revolutionized cancer treatment but frequently induce thyroid dysfunction as the most common endocrine immune-related adverse event (irAE). Baseline thyroid autoantibodies have been implicated as potential risk factors, yet the dose-response relationship between antibody titers and hypothyroidism risk, and the differential predictive value of thyroperoxidase antibody (TPOAb) versus thyroglobulin antibody (TGAb) titers, remain incompletely characterized.

METHODS

We conducted a retrospective analysis of 627 patients with various malignancies who received PD-1 inhibitor therapy between 2015 and 2025. Thyroid function and autoantibodies (TPOAb, TGAb) were monitored every 3 weeks. Antibody titers were analyzed both as continuous variables and as ordinal strata. Univariate and multivariate logistic regression analyses were performed; receiver operating characteristic (ROC) curve analysis was used to determine optimal titer cutoffs, and a predictive model was constructed and evaluated. Kaplan-Meier survival analysis assessed prognostic implications.

RESULTS

Hypothyroidism occurred in 247 patients (39.4%), with onset at a median of 12.0 weeks. In multivariate analysis, baseline TPOAb positivity (OR = 3.681, 95% CI: 2.237-6.056, P < 0.001) and TGAb positivity (OR = 4.635, 95% CI: 2.335-9.200, P < 0.001) were independently associated with hypothyroidism risk. When analyzed as continuous variables, each 100 IU/mL increase in TPOAb conferred an OR of 2.699 (P < 0.001), and each 100 IU/mL increase in TGAb conferred an OR of 1.516 (P = 0.007). Dose-response analysis revealed progressive escalation of hypothyroidism rates with increasing antibody titers: for TPOAb, 30.7% (normal), 34.9% (mild, 10-49 IU/mL), 52.2% (moderate, 50-99 IU/mL), 69.6% (high, 100-499 IU/mL), and 77.5% (very high, ≥500 IU/mL); for TGAb, 34.1% (normal), 89.3% (mild, 80-199 IU/mL), 64.3% (moderate, 200-499 IU/mL), and 72.5% (high, ≥500 IU/mL). ROC analysis identified optimal titer cutoffs of 14.5 IU/mL for TPOAb (AUC = 0.647) and 11.5 IU/mL for TGAb (AUC = 0.588); the combined predictive model achieved an AUC of 0.718.

DISCUSSION: Baseline thyroid autoantibody titers demonstrate a clear dose-response relationship with hypothyroidism risk following PD-1 inhibitor therapy. TGAb positivity, even at mildly elevated titers, confers exceptionally high risk. The optimal TGAb cutoff of 11.5 IU/mL, substantially below conventional thresholds, suggests that even low-level TGAb may indicate clinically relevant subclinical autoimmunity.