Molecular characterisation of telitacicept response phenotypes in systemic lupus erythematosus: an exploratory integrated transcriptome and B-cell receptor repertoire profiling study

Telitacicept, a dual BAFF/APRIL inhibitor, has shown clinical efficacy in systemic lupus erythematosus (SLE), but the underlying molecular mechanisms remain incompletely understood. We performed an integrative longitudinal study in ten patients with SLE before and after telitacicept treatment, alongside ten healthy controls. Paired transcriptome RNA sequencing and dedicated B-cell receptor (BCR) sequencing and repertoire analysis were integrated with serial clinical phenotyping including SLEDAI-2 K, anti-dsDNA antibodies, and complement C3/C4 levels over 12 months of follow-up. Differential expression analysis, pathway enrichment, cell deconvolution, and BCR clonal tracking were conducted. Telitacicept treatment was associated with reduced B-cell clonal diversity and decreased estimated plasma cell abundance, alongside partial reconstitution of naive B cells. Downregulation of PI3K-Akt and NF-κB pathway genes was observed. BCR repertoire analysis suggested loss of 58.7% of clones expressing IGHV4-34, IGHV3-30, and IGHV1-46, which correlated positively with baseline disease activity scores. An unexpected upregulation of interferon-stimulated genes (ISGs) was noted post-treatment, a signature not observed in independent cohorts receiving standard-of-care therapies. Exploratory subgrouping based on ISG dynamics suggested potential differences in clinical trajectory: the ISG-upregulated subgroup showed a more pronounced initial reduction in SLEDAI-2 K scores at three months, followed by a subsequent increase in disease activity scores during extended follow-up, whereas the non-upregulated subgroup maintained relatively stable scores. These preliminary findings suggest that telitacicept may remodel the B-cell repertoire while concurrently modulating interferon pathways in SLE. The observed ISG upregulation generates hypotheses regarding post-treatment immune dynamics that warrant validation in larger, independent cohorts.