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

• Published in: Scientific reports Vol. 14; no. 1; pp. 24598 - 11
• Main Authors: Sanchez, Concepcion, Campeau, Anaamika, Liu-Bryan, Ru, Mikuls, Ted R., O’Dell, James R., Gonzalez, David J., Terkeltaub, Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/256; 692/53/2422; Aged; Allopurinol; Animals; Blood Proteins - metabolism; Bone marrow; Cell activation; Complement activation; Complement System Proteins - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Febuxostat; Febuxostat - pharmacology; Febuxostat - therapeutic use; Female; Gout; Gout - blood; Gout - drug therapy; Gout - metabolism; Gout Suppressants - pharmacology; Gout Suppressants - therapeutic use; Humanities and Social Sciences; Humans; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Leukocytes (mononuclear); Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Middle Aged; multidisciplinary; Peripheral blood mononuclear cells; Proteins; Proteomes; Proteomics; Proteomics - methods; Rheumatism; Science; Science (multidisciplinary); Uric acid; Uric Acid - blood; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; Febuxostat; Allopurinol; Gout; Proteomics; Xanthine oxidase; Inflammation; Complement; TGFbeta
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-74154-5

Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts ( n  = 19, n  = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins ( p  < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Sera demonstrated altered complement activation and regulatory gene ontology biologic processes. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat treatment decreased complement activation biologic process proteins in cultured BMDMs. Reduced gout flares are linked with a XOI treatment-emergent serum protein interactome that includes inflammation regulators, associated with altered complement activation and regulatory biologic processes. Serum and leukocyte proteomics could help identify when gouty inflammatory processes begin to subside in response to ULT. Trial Registration : ClinicalTrials.gov Identifier NCT02579096, posted October 19, 2015.