Targeted Horizons in Systemic Lupus Erythematosus (SLE): A Comprehensive Review of Passive Immunotherapy from Monoclonal Antibodies to Anti‑Idiotype Networks

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease driven by dysregulated B‑cell activation, autoantibody production, and type I interferon signalling. For decades, treatment relied on non‑specific immunosuppressants and corticosteroids, which carry substantial toxicity and often fail to control disease. The past two decades have seen a paradigm shift with the emergence of passive immunotherapies that precisely target pathogenic pathways. This review provides a comprehensive overview of passive immunotherapy for SLE, covering monoclonal antibodies targeting B cells (rituximab, obinutuzumab, belimumab), cytokine pathways (anifrolumab), co‑stimulatory molecules, and emerging cellular therapies including CAR‑T cells. Recent network meta‑analyses show that telitacicept (odds ratio [OR] 5.2 for SRI‑4 response), anifrolumab (OR 1.6 for BICLA), and deucravacitinib (OR 1.6 for BICLA) are superior to standard therapy in moderate‑to‑severe SLE. The Phase III TULIP‑SC trial of subcutaneous anifrolumab achieved a 56.2% BICLA response rate vs. 37.1% for placebo (p=0.0002), with 29.0% attaining DORIS remission. The REGENCY Phase III trial of obinutuzumab in proliferative lupus nephritis demonstrated a complete renal response rate of 46.4% vs. 33.1% (p=0.02). A distinctive emerging frontier is the revival of anti‑idiotype antibody therapy—rooted in Jerne’s network theory—which aims to neutralise pathogenic autoantibodies or selectively eliminate autoreactive B‑cell clones, as supported by murine models and natural anti‑idiotypes in IVIg. Despite these advances, disease heterogeneity and the lack of standardised definitions for refractory SLE remain major challenges. CAR‑T therapy has shown encouraging early remission rates in refractory SLE, though long‑term safety and durability are uncertain. This review synthesises mechanisms, clinical evidence, safety profiles, guideline recommendations, and future directions, highlighting the potential of precision immunotherapies—including anti‑idiotype strategies—to achieve sustained remission in SLE.