Clinical bottom line
Neutrophil extracellular traps (NETs) have emerged as key contributors to the pathogenesis of multiple autoimmune diseases by promoting inflammation and tissue damage. Emerging therapies targeting NET formation or promoting NET clearance represent a promising but still investigational approach. Early-phase clinical trials and preclinical studies suggest potential efficacy in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ANCA-associated vasculitis (AAV). However, safety profiles and long-term outcomes remain incompletely characterized. Current evidence supports cautious optimism, with these therapies warranting further validation in larger, controlled clinical trials before routine clinical adoption.
What the evidence shows
NETs are web-like structures composed of DNA, histones, and neutrophil granule proteins released during neutrophil activation. They contribute to autoimmunity by exposing autoantigens, activating plasmacytoid dendritic cells, and inducing type I interferon responses [1]. Elevated NET formation and impaired NET clearance have been documented in SLE, RA, AAV, and psoriasis [2].
Therapeutic strategies under investigation include inhibitors of NETosis pathways (e.g., PAD4 inhibitors that block histone citrullination), DNase therapies to degrade NETs, and agents modulating neutrophil activation. A 2021 systematic review highlighted several PAD4 inhibitors demonstrating efficacy in reducing disease activity and NET burden in murine lupus models, with early-phase human trials underway [3]. Recombinant human DNase I, approved for cystic fibrosis, has been repurposed in small SLE cohorts showing reductions in circulating NETs and inflammatory markers, though clinical endpoints remain exploratory [4].
In AAV, a phase 2 trial of a PAD4 inhibitor showed trends toward decreased relapse rates and improved renal function, but was underpowered for definitive conclusions [5]. Similarly, RA patients treated with NET-targeting agents exhibited reductions in joint inflammation biomarkers in pilot studies, though clinical improvements were modest and transient [6].
Safety concerns include potential impairment of host defense against infections, given NETs’ role in trapping pathogens. No serious infections were reported in early trials, but longer follow-up is needed. Off-target effects and immunogenicity of biologic NET inhibitors remain theoretical risks.
Caveats and uncertainty
- Most data derive from preclinical models or small, early-phase human studies with limited sample sizes and heterogeneous populations.
- Clinical endpoints often rely on surrogate markers (NET levels, inflammatory cytokines) rather than robust clinical outcomes.
- Long-term safety, particularly infection risk and immune dysregulation, is not yet established.
- Optimal patient selection, dosing, and combination with existing immunomodulators require clarification.
- NET biology is complex and context-dependent; inhibiting NETs may have variable effects across different autoimmune diseases or disease stages.
- Current guidelines do not yet incorporate NET-targeted therapies due to insufficient evidence.
How this may change practice
If ongoing and future phase 3 trials confirm efficacy and safety, NET-targeted therapies could become adjunctive options for refractory autoimmune diseases characterized by excessive NET formation, such as SLE and AAV. They may offer a novel mechanism distinct from broad immunosuppression, potentially reducing steroid dependence and organ damage. Clinicians should remain aware of emerging data and consider enrollment of eligible patients in clinical trials. Biomarker-guided approaches measuring NET activity may eventually aid in patient stratification and treatment monitoring. Until more definitive evidence is available, NET-targeting agents should not replace established therapies outside research settings.