Table 1.

Summary of studies addressing the potential mechanisms of metformin, dipyridamole, N-acetylcysteine and statins in alleviating SLE-related disease activity and damage.

Author(s) [Ref]	Year	Type of Study	Summary of Mechanism/Results
Metformin
Yin, Y.; et al. [27]	2015	Animal study	Results in reduction in germinal centre B cells, severity of renal pathology and terminal serum ANAs Combination with 2DG is required to normalise chronically activated CD4+ T cells
Yin, Y.; et al. [26]	2016	Animal study	Normalises glucose metabolism of CD4+ T cells by inhibiting mitochondrial complex I and oxygen phosphorylation Reduces activation, proliferation and differentiation of CD4+ T cells
Lee, S.Y.; et al. [25]	2017	Animal study	Inhibits differentiation of B cells Inhibits production of Th17 via AMPK/mTOR/STAT3 pathway Increases p53 expression, which directly suppresses Th17 differentiation Decreases serum levels of anti-dsDNA, total IgG and serum IgG1
Wang, H.; et al. [12]	2015	Human study (NCT02741960; active, not recruiting)	Downregulates NET mtDNA-PDC-IFNα pathway Decreases NET DNA release via decrease in ROS production Decreases number of mtDNA copies in NET and inhibits CpG or mtDNA/anti-mtDNA autoantibody-stimulated plasma dendritic cell IFN-α
Dipyridamole
Kyttaris, V.C.; et al. [41]	2011	Human study (NCT01781611; recruiting)	Inhibits calcium-dependent signalling events in the calcineurin/NF-AT pathway Prevents activation and proliferation of SLE T cells, along with production of proinflammatory cytokines Decreases T cell-directed B cell immunoglobulin production Delays lupus-related pathology
N-Acetylcysteine
Suwannaroj, S.; et al. [50]	2001	Animal study	Decreases ROS and anti-dsDNA antibody levels Prolongs survival
Kudaravalli, J.; et al. [52]	2011	Animal study	Decreases CRP and MDA levels Improves endothelial dysfunction
Kim, J.Y.; et al. [53]	2013	Animal study	Aborts osteoprotegerin-induced apoptosis of endothelial progenitor cells
Wang, G.; et al. [51]	2014	Animal study	Reduces TCE-induced nitrosative stress Increases levels of glutathione Decreases levels of iNOS, NF-κB p65, nitrotyrosine and autoantibodies (ANA, AHA)
Shi, D.; et al. [58]	2014	Animal and human study	Decreases intracellular ROS Results in improvements in polymerisation of F-actin and migration and homing capacity of bone marrow MSCs Significantly reduces serum autoantibody levels and improves lupus nephritis
Lai, Z.W.; et al. [46]	2012	Human study (NCT00775476; suspended—funds exhausted)	Decreases levels of ROS with increased levels of glutathione in peripheral lymphocytes, resulting in sparing of NADPH Decreases activation of mTOR pathway in T cells due to changes in mitochondrial hyperpolarization Decreases DNTC and hence anti-dsDNA levels Increases FoxP3 expression in CD4+CD25+ T cells
Doherty, E.; et al. [48]	2014	Human study	Blocks ETC complex I activity, with reduction in H2O2 production
Perl, A.; et al. [47]	2015	Human study (NCT00775476; suspended—funds exhausted)	Spares NADPH, resulting in increased catabolism by kynurenine hydroxylase Decreases kynurenine levels and hence inhibits mTOR pathway
Statins
Lawman, S.; et al. [91]	2004	Animal study	Down-modulates MHC-II expression on monocytes and B cells Reduces serum IgG anti-dsDNA antibodies and proteinuria
Aprahamian, T.; et al. [70]	2006	Animal study	Increases in STAT6 and decrease in STAT4 activation Reduces inflammatory cytokines (including IL-4 and IL-10) Decreases apoptotic debris in lymph nodes, lymphoproliferation, ANA production and proteinuria
Jury, E.C.; et al. [75]	2006	Human study	Reduces Lck activation, restoring Lck expression to normal levels Reduces rapid formation of immune synapses Reverses lipid raft-associated signalling abnormalities Reduces IL-6 and IL-10
Ferreira, G.A.; et al. [78]	2010	Human study	Decreases plasma CXCL9
Amuro, H.; et al. [81]	2010	Human study	Reduces synthesis of mevalonate and inhibition of CpG induced phosphor-p38 MAPK expression Inhibits PI3-kinase pathway and IRF-7 nuclear translocation in PDCs Inhibits geranylgeranyl transferase and Rho kinase Reduces type 1 IFN-α and TNF-α by PDCs
Ruiz-Limon, P.; et al. [66]	2015	Human study	Decreases serum cytokines and chemokines (e.g., IL-6, IL-8) Increases mitochondrial biogenesis and reduces ROS levels
Ferreira, G.A.; et al. [82]	2016	Human study	Decreases sTNFR1, which is involved in anti-apoptotic/inflammatory signalling Positively correlates between sTNFR1 and SLEDAI, as well as SLICC
Houssen, M.E.; et al. [86]	2016	Human study	Increases levels of sTLR2 possibly by inhibiting Rho pathway Reduces efficiency of TLR2 signalling
Rozo, C.; et al. [69]	2017	Human study	Reduces production of interleukins (IL-17, IL-21) by disrupting activation of RhoA and inhibiting ROCK pathway