Table 3.

Potential therapies targeting LDNs or NET formation in SLE^a

Drug	Mechanism of action	Effect on neutrophils/NETs	Effect on disease/clinical use
Chloroquine/hydroxychloroquine	Unknown	Chloroquine inhibits NETosis in SLE LDNs in vitro	Antimalarials used as first‐line treatment in SLE
Colchicine	Possibly via inhibition of tubulin polymerization	Inhibits spontaneous NETosis in Behçet's syndrome HDNs in vitro	Used to treat SLE pericarditis
Cyclosporine	Modulates calcium‐dependent signal transduction by calcineurin inhibition	Inhibits ionomycin‐ and IL‐8–induced NETosis in healthy donor HDNs in vitro	Used to treat membranous lupus nephritis
DNase I	Enzymatic degradation of DNA	Enzymatic degradation of NET‐DNA	Well tolerated in phase I study in 17 patients with lupus nephritis
Eculizumab	Monoclonal antibody against complement C5 to inhibit the cleavage of C5 to C5a and C5b, possibly via reduction of C5a‐primed neutrophils for NETosis	ANCA‐induced NETosis in C5a‐primed healthy donor HDNs in vitro	Used to treat SLE patients with thrombotic microangiopathy
Idebenone	Antioxidant that protects cells against ROS toxicity, improves mitochondrial physiology	Inhibits spontaneous NETosis in SLE LDNs but not SLE HDNs in vitro	Reduced disease activity and organ damage in lupus mouse models
Metformin	Unknown	Decreases NET‐DNA and NET‐mtDNA from healthy donor HDNs in vitro	Open‐label study showed reduced SLE flares and steroid‐sparing effect
N‐acetylcysteine	Free radical scavenger	Inhibits NETosis and free radical formation from healthy donor HDNs in vitro	Well tolerated in phase I study in 36 SLE patients, with reduction in ADHD Self‐Report Scale scores
Tofacitinib	JAK1 and JAK3 inhibitor	Decreases NETosis in bone marrow HDNs obtained from MLR/lpr mice treated with tofacitinib	Well tolerated in a phase Ib/IIa study in 30 SLE patients, with reduction in circulating LDNs in tofacitinib‐treated group
Rituximab (followed by belimumab)	Rituximab: monoclonal antibody against CD20; belimumab: monoclonal antibody against BAFF	Decreases spontaneous NETosis in SLE HDNs ex vivo by reducing autoantibodies	Rituximab followed by belimumab was safe in a phase II study, with clinical responses in patients with severe refractory SLE
Vitamin D	Unknown	1,25(OH)2D3 decreases NETosis in SLE HDNs in vitro	Meta‐analysis of RCTs showed that vitamin D supplementation in SLE is safe and may improve fatigue

^aHDNs = high‐density neutrophils; ANCA = antineutrophil cytoplasmic antibody; ADHD = attention deficit hyperactivity disorder; RCTs = randomized controlled trials (see Table 1 for other definitions).