Fatigue in Inactive Auto-Inflammatory Diseases and Opportunities for Optimizing Clinical Care: A Single-Center Observational Study

<b>Objective:</b> To characterize debilitating fatigue in children and adults across inactive auto-inflammatory diseases (AID), identifying distinct disease-specific fatigue phenotypes and modifiable risk factors is necessary for optimal care. <b>Methods:</b> A single-center 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. <b>Results:</b> 66 patients were included: 39 (59%) were children; the median age at symptom onset was 4 years, at treatment start was 8 years, and study follow-up was 7 years. All patients had inactive disease at the last visit. Patients with cryopyrin-associated periodic syndromes (CAPS) had the highest Cognitive Fatigue scores (<i>p</i> = 0.04). Univariate analyses identified higher fatigue scores (1) in adults across all domains except Sleep/Rest (all <i>p</i> ≤ 0.002), (2) in patients with pathogenic/likely pathogenic variants, and (3) for disease duration ≥10 years except Sleep/Rest (all <i>p</i> ≤ 0.01). Depression was the single most important factor associated with fatigue in all domains (<i>p</i> < 0.001). In multivariable analysis, depression remained the strongest predictor of fatigue even when accounting for age, gene variant, disease duration, and treatment delay. <b>Conclusions:</b> Fatigue remains the major burden in AID despite the 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.