Risk Stratification and Patient Trajectories in CAPS: The Important Role of the Autoinflammatory Disease Damage Index

Objective: Persistent inflammation in cryopyrin-associated periodic syndromes (CAPS) causes cumulative organ damage, quantified by the Autoinflammatory Disease Damage Index (ADDI). We evaluated the ADDI for risk stratification and assessed risk trajectories under treat-to-target (T2T) management. Methods: This retrospective analysis of prospectively collected single-centre registry data included consecutive paediatric patients diagnosed with CAPS between 2007 and 2024 with ≥24 months of follow-up. The ADDI was scored at the initial damage assessment, 6 months after the first assessment at our centre (baseline), and at the last visit, and patients were assigned to predefined mild, moderate and severe risk strata. Results: Of 71 patients (56% female; median follow-up 7 years), 23 (32%) had damage at the initial damage assessment, most frequently auditory (24%), developmental (14%) and ocular (11%). ADDI scores were higher in patients with pathogenic/likely pathogenic NLRP3 variants (median 2 vs. 0; p < 0.001) and increased across phenotypes (FCAS 0, MWS 0, CINCA/NOMID 9; p < 0.001). Risk strata remained unchanged in 69 patients (97%). Two children progressed from mild to moderate risk due to progression of sensorineural hearing loss; both were non-adherent to anti-IL-1 therapy, and neither showed increased disease activity at the last visit. Conclusions: In paediatric CAPS, early cumulative damage was common and associated with phenotype and NLRP3 variant pathogenicity. Under T2T management, ADDI risk strata remained largely stable. Although based on few patients, the damage progression captured by the ADDI, but not reflected by conventional disease activity measures at the time of assessment, supports a complementary role of the ADDI in longitudinal outcome monitoring.