Preclinical Efficacy of Omega-3 Fatty Acids for Maintaining Remission of Lupus Nephritis After Intensive Immunosuppressive Therapy

This project evaluates whether dietary supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) can prolong remission of lupus nephritis (LN) after intensive immunosuppressive induction therapy and reduce reliance on long-term glucocorticoids. Using a silica-accelerated lupus nephritis (SALN) preclinical model in lupus-prone NZBWF1 mice, researchers induced disease by intranasal silica exposures beginning at 8 weeks of age and monitored animals until clinical LN developed at 21 weeks. At that point mice received weekly cyclophosphamide (CYC) injections or vehicle for eight weeks; during the CYC induction phase animals were fed either a control diet, a DHA-containing diet (human equivalent dose [HED] = 5 g/day), a moderate prednisone (PDN) diet (HED = 9 mg/day), or a combined DHA+PDN diet. The CYC regimen used a human-equivalent dose (HED = 31 mg/day) intended to model intensive immunosuppressive induction therapy. Disease activity and remission durability were assessed by serial measures of proteinuria, autoantibody levels, survival, and - six weeks after CYC cessation - multi-organ histopathology and immunohistochemistry focusing on kidney, spleen, lung, and brain.

Control (vehicle-treated) mice developed severe LN with early mortality, while CYC-treated mice experienced temporary disease suppression but commonly relapsed after cessation of CYC when maintained on control or PDN-only diets. Dietary DHA, administered alone or together with PDN during and after CYC induction, increased tissue omega-3 levels and extended the duration of remission compared with control diet or PDN monotherapy. Although PDN and DHA monotherapies each improved survival relative to control-fed CYC-treated mice, co-therapy with DHA+PDN was most effective at sustaining remission. This superiority of the combined regimen was reflected in reduced histopathologic markers of lupus severity across multiple organs examined at necropsy.

The study's findings indicate that DHA supplementation can augment the durability of CYC-induced remission in this preclinical LN model and that combining DHA with a moderate dose of prednisone offers optimal maintenance of remission. These data support the concept that omega-3 fatty acid supplementation may serve as a glucocorticoid-sparing adjunct to conventional immunosuppressive therapy, potentially reducing glucocorticoid burden while helping to prevent relapse. The researchers emphasize measurement of multiple disease metrics, including proteinuria, autoantibodies, survival outcomes, tissue omega-3 incorporation, and multi-organ histopathology, ”to provide a comprehensive evaluation of remission maintenance."

Overall, the preclinical evaluation demonstrates a promising role for DHA, particularly in combination with moderate prednisone, in sustaining remission after intensive cyclophosphamide induction of LN in lupus-prone mice. The results support further consideration of omega-3 supplementation strategies as adjunctive therapies to improve remission durability and reduce long-term glucocorticoid exposure in the context of lupus nephritis, while underscoring the need for subsequent translational and clinical investigations to determine applicability in human patients.