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Abstract
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.
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1 University of California, Department of Pharmacology, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, and Collaborative Center for Multiplexed Proteomics, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
2 University of California, Division of Rheumatology, Autoimmunity and Inflammation, Department of Medicine, San Diego, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242)
3 University of Nebraska Medical Center, Department of Internal Medicine, Omaha, USA (GRID:grid.266813.8) (ISNI:0000 0001 0666 4105); Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, USA (GRID:grid.478099.b) (ISNI:0000 0004 0420 0296)