Abstract
Identifying the multifactorial drivers of pain in sickle cell disease (SCD) is essential for developing targeted therapeutic strategies to reduce the substantial impairment in quality of life observed in this population. Although preclinical studies have delineated cellular and molecular pathways through which chronic physiological stress contributes to vaso-occlusive episodes, translation to clinical settings has been limited by the absence of quantitative measures of cumulative stress burden. To address this gap, we evaluated allostatic load (AL), a composite index of multisystem physiological dysregulation, using 27 biomarkers in 129 adults with SCD and examined its association with vaso-occlusive episode frequency. We observed that elevated AL was independently associated with increased SCD-related morbidity. Individuals in the highest AL category exhibited 4.1-fold higher odds of vaso-occlusive episodes related to pain and 6.3-fold higher odds of emergency department utilization. Beyond clinical outcomes, AL was strongly associated with adverse social determinants of health, including lower employment status, reduced social support, higher poverty burden, lower educational attainment, and residence in structurally disadvantaged neighborhoods. Together, our findings are consistent with the concept of biologic embedding, whereby cumulative exposure to adverse social conditions may be associated with physiological dysregulation and amplified disease severity. In this context, AL may serve as an integrative biologic biomarker associated with adverse social determinants of health and clinical outcomes. Incorporation of AL into both research and clinical frameworks may improve risk stratification, enhance identification of high-risk individuals, and inform the development of targeted interventions addressing both disease biology and social determinants of health.