Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker

Abstract

IntroductionUntreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout flares are self-limited inflammatory reactions involving multiple mediators. This study aimed to characterise the inflammatory profiles of gout at different phases.MethodsUsing the Olink targeted proteomics, levels of 92 inflammation-related proteins were measured in plasma samples of a prospective gout population (GOUTROS), collected at gout flare (T1), the intercritical phase (T2) and after reaching the target serum urate level under urate-lowering therapy (T3). Results were validated in an independent cohort (OLT1177-05) with plasmas collected at T1 and T2. Ex vivo and in vitro experiments were performed to assess the inflammatory properties of new biomarkers.ResultsIn total, 21 inflammatory new biomarkers were differentially expressed during the three time-points of gout disease. The levels of four of these proteins (interleukin 6 (IL-6), colony-stimulating factor 1, vascular endothelial growth factor A and tumour necrosis factor superfamily 14 (TNFSF14)) were increased during gout flare in an independent cohort. IL-6 and TNFSF14 had the highest fold change in expression during T1 versus T2 or T3. TNFSF14 was produced at the inflamed joint and enhanced the inflammatory response induced by lipopolysaccharide and MSU crystal stimulation. Conversely, TNFSF14 blockade reduced the inflammatory response. Additionally, single nucleotide polymorphisms ofTNFSF14affected the ability of myeloid cells to produce inflammatory cytokines.ConclusionGout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

“…The differentially detected proteins in both these referenced targeted proteomics studies 45 were predominantly cytokines and growth factors below the detection limits of our unbiased mass spectrometry serum proteomics approach. Therefore, the design, approach, and sample size of the current study were unique and provided distinct information on the molecular signature of XOI effects on hyperuricemia in gout.…”

“…A second, recent study of the serum proteome in gout are, using the same targeted proteomics approach in two independent cohorts, identi ed four markers elevated during gout are compared to the treat to target phase and in-between are (intercritical) phase. These in ammation-mediating proteins were tumor necrosis factor superfamily 14 (TNFSF14), IL-6, colony-stimulating factor 1 and vascular endothelial growth factor A 45 .…”