Disease modification in lupus nephritis: towards a pathophysiology-based treatment paradigm

Abstract

Glucocorticoids and antiproliferative agents, such as mycophenolate and cyclophosphamide, form the backbone of current therapy for lupus nephritis. Despite their ability to suppress inflammation, such treatments are often limited by their incomplete efficacy, substantial toxicity and failure to prevent disease progression. Many patients continue to relapse and accumulate kidney damage, underscoring the urgent need for new strategies. Advances in our understanding of the pathophysiology of lupus nephritis have provided insights into the mechanisms by which the impaired clearance of nuclear self-antigens drives innate immune activation, including excessive Toll-like receptor signalling, interferon pathway upregulation and B cell hyperactivation. These processes sustain autoantibody production and complement activation and contribute to progressive tissue injury. Emerging immunomodulatory therapies that are designed to target these pathways have the potential to restore immune balance, dampen systemic inflammation and protect the kidneys. These developments pave the way for a new treatment paradigm that focuses on disease modification, enabling early prevention of inflammation-driven kidney injury and protecting against disease progression. Fast-acting glucocorticoids and classic antiproliferative agents can be used to rapidly control systemic inflammation, although the early addition of immunomodulatory drugs is critical to promote sustained remission and prevent kidney damage. Integrated into a multitargeted, pathophysiology-based and personalized approach, this paradigm represents a departure from the conventional trial-and-error strategy of therapeutic switching and add-on regimens, and instead provides a more precise and effective framework for optimizing and individualizing disease management. This Review provides an overview of the pathophysiology of systemic lupus erythematosus as well as drugs that have been developed to target these pathophysiological processes. The authors also synthesize a translational approach aimed at enabling disease modification in lupus nephritis through the integration of glucocorticoids and conventional antiproliferative agents with immunomodulatory drugs.