ion in sufferers with secondary progressive multiple sclerosis in a randomized controlled trial (163, 164). Statins have also been tested in SLE to treat inflammation and dyslipidemia, with mixed outcomes. Some studies show beneficial effects including improved lipid and inflammatory cytokine levels and reductions in vascular inflammation, atherosclerotic plaque progression, mortality, and morbidity (16568). Nonetheless, statins haven’t met their key endpoint in clinical trials, like the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trialJ Clin Invest. 2022;132(2):e148552 doi.org/10.1172/JCIThe Journal of Clinical Investigationin kids (169) as well as the Lupus Atherosclerosis Prevention Study (LAPS) in adults (170). Interestingly, although the LAPS 2-year PKCĪ· supplier intervention trial didn’t meet the atherosclerosis main and secondary endpoints, considerable changes in lipid profiles [lipoprotein(a) and total cholesterol] were reported. Troubles in stratifying sufferers depending on their initial dyslipidemia status as well as their background medication could be the reason for this. Recent studies of lipoprotein taxonomy in sufferers with adult and juvenile-onset SLE (171, 172) and many sclerosis (173) have highlighted the heterogeneity in patient lipoprotein profiles. Hence, baseline lipid levels could possibly be important predictors of therapeutic advantage, as has been shown in RA patients treated with tocilizumab and JAK inhibitors, among whom patients with increased lipid levels had a greater response to lipid-lowering drugs (107, 135). Other therapies targeting lipid metabolism include reconstituted HDL (shown to lessen plaque in lipid content, macrophage size, and inflammation; ref. 174) and also the recently approved statin alternative inclisiran, which increases LDLR levels in the liver (by inhibiting proprotein convertase subtilisin/kexin kind 9, the enzyme accountable for LDLR inhibition), thereby reducing LDL-C in the blood by as much as 50 , similarly to high-dose statins (175). Inside the future, new lipid-modifying drugs might be utilised as an option to, or in combination with, statins for sufferers with AIRDs and dyslipidemia not controlled by conventional remedy and at higher danger of cardiovascular events, particularly in those on antiinflammatory treatments that exacerbate dyslipidemia as discussed above. Some immune receptors that nNOS review reside in lipid rafts are targeted by AIRD remedies — such as CD20 targeted by rituximab (155), CD80/CD86 targeted by abatacept (141), and IL-6R targeted by tocilizumab (176) — suggesting that lipid modification could potentially alter the efficiency of those therapies by regulating membrane turnover of these receptor targets. Some biologic agents demand intact lipid rafts to exert their therapeutic function, e.g., rituximab (15557). Additionally, pharmacologic inhibition of lipid raft elements (cholesterol and glycosphingolipids) applying statins and glycolipid synthase inhibitors (N-butyldeoxynojirimycin) restored defective lipid raft levels and normalized in vitro function in CD4+ T cells from patients with SLE. This included T cell receptor signaling and function and anti-dsDNA antibody production by autologous B cells (ten, 177). Interestingly, elevated glycosphingolipid levels in SLE T cells have been linked with the increased expression on the LXR master lipid transcriptional regulator, which straight modulates enzymes involved in glycosphingolipid synthesis (9). Whether or not supplementa