Reducing glucocorticoid burden in lupus with omega-3 fatty acids: docosahexaenoic acid augments prednisone efficacy in maintaining cyclophosphamide-induced remission of preclinical lupus nephritis.

Managing lupus nephritis (LN) remains challenging due to relapses after immunosuppressive induction and toxicity from long-term glucocorticoid (GC) maintenance therapy. Dietary omega-3 fatty acids prevent LN onset in preclinical models, but their role in maintaining remission post-induction remains unstudied. The silica-accelerated LN (SALN) model using lupus-prone NZBWF1 mice was used to evaluate how docosahexaenoic acid (DHA), an omega-3 fatty acid, influenced LN remission durability after cyclophosphamide (CYC) induction, alone or with a moderate dose of prednisone (PDN). Mice received intranasal silica weekly from 8 to 11 weeks. After LN developed at 21 weeks, groups were injected weekly with CYC (human equivalent dose [HED] = 31 mg/day) or vehicle (VEH) for 8 weeks, during which CYC groups also received control, DHA (HED = 5 g/day), PDN (HED = 9 mg/day), or DHA+PDN diets. Disease activity was monitored via proteinuria, autoantibodies, and survival. Six weeks post-CYC, multiorgan histopathology and immunohistochemistry were assessed. VEH-treated mice developed severe LN with early death. CYC slowed disease temporarily in control- and PDN-fed mice; relapses occurred after cessation. DHA and DHA+PDN increased tissue omega-3 levels and prolonged remission. PDN and DHA monotherapies and co-therapy improved survival, but DHA+PDN was most effective at sustaining remission as reflected by reduced histopathologic markers of lupus severity in the kidney, spleen, lung, and brain. DHA+PDN optimally maintained LN remission after CYC, supporting omega-3 supplementation as a potential GC-sparing strategy to improve immunosuppressive therapy and prevent relapses.