Fatigue in Inactive Autoinflammatory Diseases: Opportunities for Care Transformation

Objective: To characterize debilitating fatigue in children and adults across inactive autoinflammatory diseases (AID), identify distinct disease-specific fatigue phenotypes, and modifiable risk factors for optimal care. Methods: A single-centre cohort of consecutive patients with inactive AID between 2007 and 2024 was performed. Demographics, clinical and laboratory features and treatment were captured. Fatigue was characterized and quantified using the PedsQL-MFS and VAS; the CES-D/CESD-R was applied to assess depression risk. Comparisons were made using non-parametric methods, multivariable regression identified risk factors of fatigue in inactive disease. Results: Sixty-six patients were included; 39 (59%) were children; median age at symptom onset was 4 years, at treatment start 8 years, and study follow-up was 7 years. All patients had inactive disease at last the visit. Patients with cryopyrin associated periodic syndromes (CAPS) had the highest cognitive fatigues scores (p=0.04). Univariate analyses identified higher fatigue scores 1) in adults across all domains except sleep/rest (all p≤0.002), 2) in patients with pathogenic/likely pathogenic variants and 3) for disease duration ≥10 years except sleep/rest (all p≤0.01). Depression was the single most important factor associated with fatigue in all domains (p< 0.001). In multivariable analysis, depression remained the strongest predictor of fatigue even when accounted for age, gene variant, disease duration and treatment delay. Conclusion: Fatigue remains the major burden in AID despite availability of effective anti-inflammatory therapies. Depression was identified as the strongest determinant of debilitating fatigue in inactive AID. Systematic screening and integrated approaches addressing both psychological and inflammatory domains are essential for optimal care.