Early longitudinal proteomic changes during sirolimus therapy in tocilizumab-refractory idiopathic multicentric Castleman disease
Tomohiro Koga, Shoichi Fukui, Remi Sumiyoshi, Toshimasa Shimizu, Naoki Hosogaya, Chizu Fukushima, Hiroshi Yamamoto, Hajime Yoshifuji, Shinji Higa, Atsushi KawakamiAbstract
Objectives
To characterise early treatment-associated changes in circulating immune mediators following sirolimus initiation in patients with tocilizumab-resistant idiopathic multicentric Castleman disease (iMCD).
Methods
As a predefined translational sub-analysis of a placebo-controlled exploratory trial, we performed longitudinal serum proteomic profiling using a RayBiotech L-1000 antibody array (∼1,000 proteins) in a sirolimus-treated patient with tocilizumab-resistant iMCD. Serum samples were obtained at baseline and at weeks 8, 12, and 16. Protein expression levels were normalised, log₂-transformed, and analysed for stepwise temporal changes. Pathway-level effects were assessed using gene set enrichment analysis (GSEA).
Results
Six immune mediators—CCR5, ICAM-1, RANTES, S100A8/A9, CD40 ligand, and OX40 ligand—showed consistent monotonic decreases from baseline through week 12. Heatmap visualisation of the top 80 dynamically regulated proteins confirmed a broader suppression of immune activation signatures. GSEA demonstrated significant negative enrichment of coagulation, complement, IFN-γ response, IL-6–JAK–STAT3 signalling, TNFα signalling via NF-κB, and MMP-driven extracellular matrix remodelling. Temporal analysis confirmed sustained downregulation of IFN-γ-inducible chemokines (CXCL9, CXCL10, CXCL11) and a broad panel of interferon-response mediators through weeks 12 and 16.
Conclusions
Early and coordinated decreases in immune-inflammatory mediators were observed during sirolimus therapy in tocilizumab-resistant iMCD, extending beyond the IL-6 axis to encompass IFN-γ, TNF-α, and chemokine signalling. These findings are hypothesis-generating and provide a mechanistic rationale for mTOR inhibition as a potential disease-modifying strategy warranting evaluation in future controlled studies.