Elevated central sensitization inventory symptom burden and depressive symptoms define a clinical vulnerability phenotype in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is characterized by heterogeneous symptom burden encompassing pain, affective symptoms, and functional impairment. Although reproducible symptom phenotypes have been identified, the symptom profiles associated with the greatest functional vulnerability remain incompletely characterized. We evaluated whether elevated Central Sensitization Inventory (CSI) symptom burden and depressive symptoms jointly identify a clinically meaningful vulnerability phenotype associated with greater functional impairment. METHODS: We analyzed a harmonized multisite cohort of adults meeting the 2016 American College of Rheumatology criteria for FM. Participants completed the Central Sensitization Inventory (CSI), Beck Depression Inventory-II (BDI-II), Fibromyalgia Impact Questionnaire (FIQR/SIQR-equivalent), McGill Pain Questionnaire (MPQ), and SF-36. Multivariable linear regression models evaluated the independent associations of CSI symptom burden and depressive symptoms with multidomain functional outcomes after adjustment for relevant clinical covariates. Interaction analyses and clinical phenotype stratification were subsequently performed. RESULTS: Among 820 participants, higher CSI symptom burden was independently associated with worse Physical Functioning (β = -0.21, p < 0.001), Energy/Fatigue (β = -0.30, p < 0.001), Pain (β = -0.37, p < 0.001), and General Health (β = -0.35, p < 0.001). Greater depressive symptoms were independently associated with poorer Emotional Well-Being (β = -0.53, p < 0.001), Social Functioning (β = -0.71, p < 0.001), Physical Functioning (β = -0.30, p < 0.001), and Health Change (β = -0.33, p < 0.001). Significant CSI × BDI interactions were observed for Role Physical, Role Emotional, Energy/Fatigue, Emotional Well-Being, and Social Functioning (all p < 0.01). Participants with concomitantly elevated CSI symptom burden and depressive symptoms demonstrated the greatest impairment across functional domains. CONCLUSIONS: Elevated CSI-symptom burden and depressive symptoms identify a clinically meaningful vulnerability phenotype characterized by substantial multidomain functional impairment in FM. These findings support multidimensional clinical phenotyping as an approach for identifying patients at greatest risk for adverse functional outcomes and provide a clinically grounded framework for future investigations examining the biologic mechanisms underlying these clinically defined vulnerability states.