Ab0114 Influence of Acute Gout Flare and Serum Urate Lowering on Biomarkers of Systemic Inflammation

Background: Elevated NLRP3 inflammasome-associated biomarkers, including C-reactive protein (hsCRP),1 interleukin-6 (IL-6),2 and neutrophil-to-lymphocyte ratio (NLR),3-5 have been associated with cardiovascular disease and mortality. The NLRP3 inflammasome is activated by urate crystals and is involved in gout flare.6 As a result, polyarticular gout patients have high levels of neutrophil activation7 and gout patients are at an increasingly recognized risk for systemic inflammatory consequences. Therefore, the effect of urate lowering on body-wide inflammation is of increasing interest. Objectives: This post hoc analysis examined available inflammatory biomarkers during 52 weeks (wks) of pegloticase treatment with and without methotrexate (MTX) cotherapy. All patients were MIRROR RCT participants. Methods: Gout patients with prior inadequate response to standard therapies and ongoing gout symptoms received biweekly pegloticase (8 mg; 52 wks) plus oral MTX (15 mg/wk) or placebo (PBO) cotherapy. Pre-infusion prophylaxis included 125 mg IV methylprednisolone. A 2-wk MTX tolerance assessment and 4-wk MTX/PBO run-in preceded first pegloticase infusion (Day 1). IL-6, TNF, and hsCRP were measured at baseline (wk -6, pre-MTX exposure), Day 1, and wks 2, 4, 6, 8, 10, 12, 14, 24, 36, and 52. All available data were included (regardless of treatment status). Results: 96 patients (92% men, 56±13 yrs) received pegloticase+MTX; 49 (86% men, 53±12 yrs) received pegloticase+PBO. At baseline, mean hsCRP (6.7±11.9 mg/L n=123, normal: Figure 1). hsCRP and IL-6 returned to near-baseline levels by wk 14, and, on average, remained near or slightly below baseline through wk 52 (wk 52 hsCRP: 4.2±7.0 mg/L n=101, IL-6: 1.9±2.4 pg/mL n=98). Following pegloticase initiation, TNF decreased in patients receiving MTX co-therapy but not those receiving PBO, with changes persisting through wk 52 (wk 52 TNF: 3.5±3.4 pg/mL n=98). Inflammatory biomarker changes closely followed the occurrence of treatment-emergent gout flares (Figure 1). Conclusion: These data suggest a systemic inflammatory influence of local gout flares, as evidenced by similar trends between flare occurrence and hsCRP and IL-6 levels, known surrogates of inflammasome activation. With prolonged SU-lowering, subsequent deposited urate depletion,11,12 and flare cessation, transient increases in hsCRP and IL-6 were no longer observed and mean biomarker levels remained at/slightly below pre-treatment values. Of note, biomarker levels were highly variable between patients and further study is needed to confirm a relationship between gout flares and inflammatory biomarker levels. Nonetheless these findings, along with the known correlation between serum urate (SU) and gout flare occurrence,13 emphasize the importance of SU control in gout patient management. REFERENCES: 1 Ridker PM, et al. Lancet 2023;401:1293-1301. 2 Ridker PM, Rane M. Circulation Res 2021;128:1728-46. 3 Angkananard T, et al. BioMed Res Int 2018;2018:2703518. 4 Adamstein NH, et al. Eur Heart J. 2021;42:896-903. 5 Song M, et al. Sci Rep 2021;11:464. 6 So AK, Martinon F. Nat Rev Rheumatol 2017;13:639-47. 7 Vedder D, et al. Arthritis Res Ther 2020;22:148. 8 Mayo Clinic Labs 2022; https://www.mayoclinic.org/tests-procedures/c-reactive-protein-test/about/pac-20385228. Accessed 29 Nov 2023. 9 Mayo Clinic Labs 2023; https://www.mayocliniclabs.com/test-catalog/overview/57889#Clinical-and-Interpretive. Accessed 29 Nov 2023. 10 Mayo Clinic Labs 2023; https://www.mayocliniclabs.com/test-catalog/overview/618776#Clinical-and-Interpretive. Accessed 29 Nov 2023. 11 Dalbeth N, et al. Arthritis Rheumatol 2023;74 (suppl 9). 12 Dalbeth N, et al. Rheumatology (Oxford). 2022;61:4898-4904. 13 Shoji A, et al. Arthritis Rheum. 2004;51:321-5. Acknowledgements: NIL. Disclosure of Interests: Michael Pillinger Horizon (now Amgen, Inc.), Sobi, Fortress Biotech, Federation Bio, Scilex, Hikma, Horizon (now Amgen, Inc.), Ada Kumar Amgen, Inc., Amgen, Inc., Katie Obermeyer Amgen, Inc., Amgen, Inc., Lissa Padnick-Silver Amgen, Inc., Amgen, Inc., Brian LaMoreaux Amgen, Inc., Amgen, Inc.