Integrating B Cell Differentiation Model With Real-World Data Informs Determinants for Antibody-Secreting Cell...

Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by extensive fibrosis, vascular abnormalities, and immune dysregulation, affecting clinical outcomes such as skin thickness and pulmonary function with high mortality rates. B cells play a pivotal role in the pathogenesis of SSc. This study aimed to develop a systems model for B cell differentiation and tissue distribution to characterize the therapeutic responses to CD19⁺ (inebilizumab) and CD20⁺ cell depletion (rituximab) in patients with SSc. We integrated real-world data (RWD) of B cell subsets from 61 patients with untreated SSc using this model. Upon successful model validation, virtual clinical simulations revealed uniform dynamics of CD19 cells but distinct patterns of antibody-secreting cells (ASCs) among patients, with significant variabilities due to CD20 treatment. The ratio of plasma cells to plasmablasts (PC/PB) was identified as a crucial factor, with a high ratio correlating with a poor response to CD20 treatment but stable depletion by CD19 treatment. Furthermore, the CD20-binding affinity of rituximab and its elimination rate constant were also suggested to contribute to the therapeutic variabilities of CD20 treatment. This study addressed ASC responses as a marker of a proof-of-mechanism; nonetheless, the model must be extended to further address the aforementioned clinical outcomes. Overall, the systems model provided mechanistic insights into the contrasting responses of ASCs depending on the study drugs and identified potential predictors of treatment efficacy. By integrating RWD, our study provides a mechanistic framework to optimize dosing strategies and guide personalized treatment approaches to refine B-cell depletion therapies for SSc.