Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by dysregulated B-cell responses and type I interferon pathway activation. Telitacicept, a dual BAFF/APRIL inhibitor, has demonstrated clinical efficacy in randomised controlled trials. However, the molecular determinants underlying heterogeneous treatment responses remain poorly understood. Whether B-cell targeting inadvertently engages counter-regulatory inflammatory pathways has not been systematically investigated. Understanding these mechanisms is essential for optimising patient stratification and developing precision therapeutic strategies.

We performed an integrative longitudinal study in ten patients with active SLE (meeting ACR classification criteria) before and after 3 months of telitacicept treatment, alongside ten age- and sex-matched healthy controls. Paired whole-transcriptome sequencing and B-cell receptor (BCR) repertoire analysis were performed on peripheral blood samples collected at baseline and post-treatment. These molecular data were integrated with serial clinical phenotyping over 12 months of follow-up, including SLEDAI-2K scores, anti-dsDNA antibody titres, and complement C3/C4 levels. Transcriptomic and BCR metrics were correlated with disease activity trajectories. Key findings were validated against independent SLE cohorts from the GSE224705 dataset receiving standard-of-care therapies (mycophenolate mofetil or glucocorticoids plus hydroxychloroquine).

Telitacicept induced two distinct molecular programmes with divergent clinical associations. First, treatment selectively contracted expanded B-cell clones expressing pathogenic IGHV genes (IGHV4-34, IGHV3-21, IGHV1-46). Baseline usage of these genes correlated positively with SLEDAI-2K scores and anti-dsDNA antibody levels, and negatively with complement C3 and C4. Post-treatment, specific VJ gene pairs derived from these IGHV genes were significantly depleted, accompanied by reduced plasma cell abundance and partial restoration of naïve B cells. The Chao1 diversity index showed a significant reduction following therapy (p = 0.008), consistent with contraction of expanded clones. Second, telitacicept concurrently elicited a paradoxical upregulation of interferon-stimulated genes (ISGs) in a patient-stratified manner. This ISG signature was entirely absent in comparator cohorts receiving standard-of-care therapies. Hierarchical clustering based on longitudinal ISG expression patterns identified two subgroups: ISG-high (n = 7) and ISG-low (n = 3). Patients in the ISG-high subgroup exhibited significantly higher baseline disease activity. Despite greater initial clinical improvement at 3 months, these patients experienced subsequent increases in disease activity scores during 12-month follow-up.

Telitacicept exerts dual immunomodulatory effects in SLE: it achieves clonal-level reset of the pathogenic BCR repertoire while simultaneously triggering patient-stratified interferon pathway activation. The ISG signature identifies a subset of patients with heightened baseline disease activity who exhibit disease activity fluctuations following initial improvement. These findings provide a molecular rationale for future studies evaluating sequential JAK inhibitor combination therapy in ISG-high patients and highlight the need for larger prospective cohorts to validate these exploratory observations.