Behavioural withdrawal during an acute stress test as a marker of psychobiological vulnerability in hereditary angioedema

Introduction: Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) features clinical heterogeneity and stress-triggered attacks. Behavioral tolerance to acute stress may reveal vulnerability profiles beyond standard clinical descriptors. This study aimed to characterize stress response patterns and compare groups based on behavioral tolerance. Methods: HAE-C1INH patients underwent the Socially Evaluated Cold Pressor Test (SECPT) and were stratified as Completers or Non-completers (early withdrawal). Stress appraisal, cardiovascular parameters (heart rate, HR; systolic/diastolic arterial pressure, SAP/DAP), and plasma cytokines (IL-1β, TNF-α, IL-6) were assessed. Disease control and quality of life were measured via Angioedema Control Test (AECT) and Angioedema Quality of life (AE-QoL) questionnaires. Results: Twenty patients were enrolled (15 Completers and 5 Non-completers). Non-completers showed poorer disease control (10.6 ± 5.5 vs 14.5 ± 2.2; p ≤ 0.05) and worse AE-QoL, particularly in the Functioning (8.6 ± 4.3 vs 4.7 ± 1.7; p ≤ 0.05) and Fatigue/Mood (13.6 ± 7.1 vs 10.5 ± 3.5; p ≤ 0.05) domains. They reported higher stress (91 ± 8.9 vs 50.5 ± 33.7; p ≤ 0.05), pain (87.8 ± 12.8 vs 50.1 ± 31.3; p ≤ 0.05) and unpleasantness (83 ± 19.9 vs 49.5 ± 30.5; p ≤ 0.05) during the SECPT. Non-completers displayed an attenuated SAP response relative to Completers (128.3 ± 18.0 vs 148.9 ± 18.3 mmHg; p ≤ 0.05). Inflammatory profiles also diverged: Non-completers showed higher IL-6 levels at 40 minutes after SECPT (3.5 ± 1.1 vs 2.2 ± 0.7 pg/ml; p ≤ 0.05) and opposite TNF-α trajectories compared with Completers (0.9 ± 1.0 vs -0.5 ± 0.9 pg/ml; p ≤ 0.05). Conclusion: Early withdrawal during SECPT identifies a vulnerable HAE-C1INH subgroup with distinct psychological, cardiovascular, and inflammatory patterns.