Initiation of biologic therapy in patients with rheumatoid arthritis (RA) was associated with reductions in circulating citrullinated histone H3 (CitH3), a marker of neutrophil extracellular trap (NET)-associated activity, and carotid intima-media thickness (cIMT), alongside improvements in disease activity, inflammatory markers, and high-density lipoprotein (HDL) cholesterol, according to a recent study published in Clinical Rheumatology. The findings highlight a potential relationship between NET-associated activity, lipid metabolism, and subclinical atherosclerosis in RA.
NETs are extracellular structures released by activated neutrophils and contain DNA, histones, and neutrophil-derived proteins. They contribute to innate immune defence but may also promote autoimmune inflammation by exposing citrullinated autoantigens. NET-associated activity has also been implicated in endothelial dysfunction and atherosclerosis, potentially contributing to the increased cardiovascular risk observed in RA.
The prospective, single-arm observational study included 36 patients with RA evaluated at baseline and after 6 months of biologic therapy. Disease activity was assessed using the Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP), while inflammation was evaluated using CRP and erythrocyte sedimentation rate (ESR). CitH3 levels were measured using enzyme-linked immunosorbent assay, and cIMT was assessed by high-resolution B-mode ultrasonography. Linear regression analyses examined associations between NET-associated activity, inflammatory markers, lipid profile, and subclinical atherosclerosis.
After 6 months of treatment, significant improvements were observed in disease activity and inflammatory markers. Median DAS28 decreased from 3.59 to 2.97, CRP from 6.0 to 3.0 mg/L, and ESR from 27.5 to 13.5 mm/h (all p < 0.001). Median CitH3 levels decreased from 3.89 (0.11–32.78) to 2.56 (0.07–8.39; p = 0.025). Median cIMT also declined from 1.00 (0.7–1.6) mm to 0.75 (0.6–1.3) mm (p < 0.001). Mean HDL cholesterol increased from 56.36 ± 16.21 to 67.47 ± 17.56 mg/dL (p < 0.001), while other lipid parameters showed no significant changes.
At follow-up, CitH3 levels were independently associated with ESR (β = 0.448, p = 0.018), indicating a relationship between NET-associated activity and systemic inflammation. Longitudinal analyses showed that changes in HDL cholesterol were independently associated with changes in CitH3 (β = −0.505, p = 0.003). However, changes in DAS28, CRP, ESR, oxidised low-density lipoprotein (oxLDL), and cIMT were not independently associated with changes in CitH3.
The investigators also compared patients receiving anti-tumour necrosis factor (anti-TNF) agents with those receiving non-anti-TNF biologics. No significant differences were observed in changes in CitH3 or HDL cholesterol between the groups. However, the small and unequal subgroup sizes limited conclusions regarding treatment-class-specific effects.
The association between increased HDL cholesterol and reduced CitH3 levels raises the possibility of an immunometabolic relationship between lipid metabolism and NET-associated activity. HDL has recognised antioxidant and anti-inflammatory properties that may influence inflammatory pathways. Nevertheless, the study did not directly investigate HDL functionality or the mechanisms linking HDL to NET formation. Similarly, although CitH3 and cIMT decreased concurrently, changes in CitH3 were not independently associated with changes in cIMT, and a causal relationship cannot be established.
The findings suggest that biologic therapy may influence NET-associated activity alongside improvements in inflammatory and vascular parameters in RA. The association between changes in HDL cholesterol and CitH3 levels provides a basis for further investigation into the immunometabolic links between inflammation and cardiovascular risk. Larger, controlled prospective studies are required to confirm these observations and establish their clinical significance.
Reference
Papamichail GV, Chrysanthopoulou A, Georgiadis NA, Kapsali CA, Xydis VG, Kitsakos A, Drosos AA, Voulgari PV. Neutrophil extracellular trap suppression in rheumatoid arthritis patients treated with biologic therapy: a prospective observational study. Clin Rheumatol. 2026 Nov;45(11):6573-6581.