Abstract and Introduction
Abstract
Background: Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here.
Methods: Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments.
Results: Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR ("cough") occurred and no new safety signals were identified.
Conclusion: Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes.
Trial registration: ClinicalTrials.gov (NCT03635957)
Introduction
Hyperuricemia and gout affect 32.5 million and 9.2 million people, respectively, in the USA.[1] Chronic hyperuricemia results in monosodium urate crystal deposition throughout the body, including in the kidneys, heart, larynx, and bowel,[2] and is associated with a specific set of comorbidities, including cardiovascular disease,[3–7] hypertension,[7,8] diabetes,[7,9] and chronic kidney disease.[7,10] Even in patients with asymptomatic hyperuricemia, inflammation levels are elevated.[11,12] When oral urate-lowering therapies (ULTs), including both xanthine oxidase inhibitors[13] and uricosurics,[13,14] are not tolerated, contraindicated, or no longer effective, refractory or uncontrolled gout can occur. The clinical hallmarks of uncontrolled gout include recurrent debilitating flares, chronic synovitis, chronic gout-related pain, tophi, urate-related joint damage (as visible on radiography), and urate deposition (as visible on dual-energy computed tomography [DECT] or ultrasound imaging). Uncontrolled gout further increases the risk for cardiovascular disease, diabetes, and chronic kidney disease[15] as well as the burden on quality of life resulting from ongoing pain and high levels of disability.[16,17] Unfortunately, patients with chronic refractory gout are left with limited treatment options for urate lowering.
Pegloticase is an effective medication for treating uncontrolled gout, but some patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy[18–20] and increased infusion reactions (IRs).[18,19] In the phase 3 clinical trials, the pooled pegloticase responder rate at the approved dose regimen was 43.5% during month 6 (42% during months 3 and 6 combined),[18] with most high-titer ADA patients having loss of pegloticase efficacy within 6 months.[18] The 6-month results from the MIRROR open-label trial suggest that methotrexate (MTX) administered in conjunction with pegloticase nearly doubles the responder rate (79% during month 6 [11 of 14 patients], 95% confidence interval: 49–95%) with lower IR occurrence and otherwise similar safety profile as pegloticase monotherapy.[21] Furthermore, 12-month MIRROR open-label safety and efficacy findings indicate that urate-lowering is sustained over the long-term in patients remaining on therapy with both pegloticase and methotrexate.[22] Here, longer-term (12-month) exploratory endpoints of the MIRROR open-label trial are reported, including joint involvement, Health Assessment Questionnaire, and Global Assessments of Gout.
Arthritis Res Ther. 2022;24(281) © 2022 BioMed Central, Ltd.
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