A multi-composite disease activity score (NFKB1-DAS) for NFKB1 insufficiency

NFKB1 encodes the p105/p50 NF-κB1 transcription factor. Heterozygous mutations in NFKB1 may lead to NFKB1 insufficiency affecting multiple organ systems. This study aimed to develop an NFKB1-Disease-Activity-Score (NFKB1-DAS), serving as a tool in future clinical trials. Based on published phenotypic data from 179 patients with 77 distinct NFKB1 variants, we drafted an initial score consisting of 42 parameters. This draft was subsequently analyzed in a multicenter cohort of 41 patients with 22 distinct pathogenic NFKB1 variants. Using a Leave-One-Out (LOO) analysis (cutoff differential value: 23.07), we identified the 21 most relevant parameters to construct the final NFKB1-DAS. Calculation of the NFKB1-DAS in 31 CTLA4-deficient patients as a comparison cohort showed higher scores in NFKB1-insufficient patients (p = 0.03 (95% CI [-0.16, -0.01]) and the NFKB1-DAS correlated with hospitalization (p = 0.01; OR 2.07 (95% CI [1.18; 3.62]). However, given the optimism bias occurring when testing the score in the cohort it was developed with and the limited case numbers, validation of the NFKB1-DAS in an unrelated cohort remains essential. Analysis of the NFKB1-DAS in patients with variants of unknown significance (VUS) in NFKB1 (n = 14) showed individual patients reaching high scores. Future studies could evaluate a possible utility of the score in assessing VUS pathogenicity. Ultimately, the proposed NFKB1-DAS represents a first step toward monitoring disease activity and treatment response in future clinical trials in NFKB1 insufficiency.