Targeted therapies in systemic lupus erythematosus: mechanistic insights and clinical evidence from phase II and III trials

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease characterised by autoantibody production and dysregulated B- and T- cell activation, resulting in multisystem involvement. Despite therapeutic advances, persistently active and corticosteroid-dependent disease remain a significant clinical challenge. This systematic review will analyse targeted therapies in phase II and III clinical development. We conducted a systematic review of multicentre, randomised, placebo or standard of care-controlled phase II and phase III clinical trials investigating novel targeted and biological therapies in patients with SLE. Both peer-reviewed publications and registered international clinical trials were included (search date: from 2000–January of 2026). A total of 90 targeted agents were identified, including 70 biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) and 20 targeted synthetic DMARDs (tsDMARDs), across 770 assessed clinical trials. Of these, 67 agents had reached phase II and 23 phase III in their clinical development. At the time of writing trials were classified as completed ( n  = 45), active and recruiting ( n  = 9), active but not recruiting ( n  = 7), active not yet recruiting ( n  = 5), terminated ( n  = 23) and withdrawn ( n  = 1). The treatment of SLE is rapidly evolving towards targeted, mechanism-based interventions. Emerging therapies directed at specific immune pathways offer the potential to reduce disease activity, minimise corticosteroid use and prevent organ damage. On-going investigation of promising agents in Phase II and III trials remains essential to confirm short and long-term efficacy, safety, and optimal patient selection, facilitating the time when meaningful personalised treatment strategies in SLE can become a reality.