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Lupus nephritis is the most common organ threatening manifestation of systemic lupus erythematosus (SLE), and is associated with significant morbidity and mortality, including increased risks for end stage kidney disease (ESKD) and cardiovascular disease. Regular screening for and early diagnosis and treatment of lupus nephritis are paramount for minimizing loss of nephron mass and improving long-term kidney health. Following the pivotal trials conducted by the National Institutes of Health, the treatment of lupus nephritis has traditionally been divided into an ‘induction/initial’ phase and a ‘maintenance/subsequent’ phase, in which high- dose glucocorticoids are paired with cyclophosphamide or high dose mycophenolate for 3–6 months and then followed by lower doses of glucocorticoids with lower doses of mycophenolate or azathioprine for at least 3–5 years. Disappointingly, we have learned that these therapeutic regimens are suboptimal and continue to be associated with unacceptably high rates of damage accrual, lupus nephritis flares, and ESKD. 1 Against this background, we find ourselves amid a paradigm shift in the treatment of lupus nephritis, propelled by the successful trials and subsequent approvals of belimumab and voclosporin. As described in the 2024 ACR Guideline for the Screening, Treatment, and Management of Lupus Nephritis, the currently recommended therapeutic approach entails the use of combination immunosuppressive therapy, so called ‘triple immunosuppressive therapy.’2 This regimen includes glucocorticoids plus the addition of two immunosuppressive therapies, anchored on either belimumab or voclosporin.3 4 Glucocorticoids should be administered initially as intravenous pulses, followed by a starting oral dose of ≤0.5 mg/kg/d, with a subsequent taper to ≤5 mg/d by 6 months.2 The goal of therapy is achievement of complete renal response with proteinuria ≤0.5 g and improvement/stabilization of kidney function by 6–12 months. After achievement of a complete renal response, total duration of immunosuppressive therapy should be at least 3–5 years. The hope is that the recommendations in this updated guideline will lead to our aim of improving the health outcomes and quality of life for all those living with lupus nephritis.Learning Objectives At the end of this presentation participants will be able to:Discuss the major limitations of our conventional therapies for lupus nephritisDescribe the evolving treatment paradigm for lupus nephritis, including the concept of triple immunosuppressive (combination) therapyApply the concept of triple immunosuppressive therapy to their patients with lupus nephritisReferences Figueroa-Parra G, Cuéllar-Gutiérrez MC, González-Treviño M, et al. Impact of glucocorticoid dose on complete response, serious infections, and mortality during the initial therapy of lupus nephritis: a systematic review and meta-analysis of the control arms of randomized controlled trials. Arthritis Rheumatol. 2024;Sep;76(9):1408–18. doi: 10.1002/art.42920Sammaritano LR, Askanase A, Bermas BL, et al. 2024 american college of rheumatology (acr) guideline for the screening, treatment, and management of lupus nephritis. Arthritis Rheumatol. 2025 doi: 10.1002/art.43212Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117–28. doi: 10.1056/NEJMoa2001180Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (aurora 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070–80. doi: 10.1016/s0140-6736(21)00578-x