NLRP3 Inflammasome-Related Gene Expression in Patients with Inactive Lupus Nephritis Treated with Dapagliflozin

Background: Recent studies suggest that the SGLT2i reduce inflammatory response, including modulation of the NLRP3 inflammasome that secretes pathogenic inflammatory cytokines. This study is an exploratory analysis of the dapagliflozin in inactive lupus nephritis (LN) randomized crossover trial that aimed to analyze expression of IL1B, IL18 and NLRP3 genes and interleukin (IL)-1β. Methods: For the trial we recruited LN class III, IV (+/-V) patients without active LN but with residual, in the maintenance treatment with RAASi and MMF<2g/day no steroids. Those included were randomized to receive dapagliflozin 10mg on top of standard of care therapy (SoC) or not. After 24w the groups were crossed over and those without dapagliflozin received it for the next 24 weeks. Primary endpoint is reduction of proteinuria (6 and 12 mo). Exploratory endpoints were RNA expression and cytokines levels with and without dapagliflozin in adequate samples (N=16). Exploratory analysis included gene expression assays performed with TaqMan® fluorogenic probes to genes IL1B, IL18 and NLRP3 and IL-1β concentrations using BD Human Inflammatory Cytokine CBA. Results: From 97 screened LN patients, we excluded 67 due to active LN, proteinuria than 500mg/d or eGFR<20ml/min. We included 30 patients that were randomized 14 to start the treatment with dapagliflozin on top of SoC and 16 to remain with the usual therapy for 24w. Nine patients were excluded from the analysis due to new LN flare or lost to f/u. Final analysis shows a significant reduction in the proteinuria of –36.1% after 6mo of dapagliflozin as opposed to a –3.5% for those in the SoC therapy at the end of a 6mo period, p=0.03. The expression of IL1B and IL18 did not show significant difference, but NLRP3 expression was increased (FC = 3.2; p = 0.004) and serum levels of IL-1β were reduced (3.70 pg/mL to 3.57 pg/mL; p= 0.02), when the patients received the dapagliflozin. Conclusion: We demonstrate a significant reduction in residual proteinuria in patients with inactive LN with dapagliflozin. NLRP3 gene expression was increased and IL-1β levels were lower with dapagliflozin in inactive LN patients under stable immunosuppression, that might be explained by post-transcriptional mechanisms. Funding: Government Support – Non-U.S.