Troum Orrin M, Botson John K, Obermeyer Katie, Chao Bo, Song Yang, Zarzoso Jennifer, Gutierrez Kjerstina, Verma Supra, Padnick-Silver Lissa, LaMoreaux Brian
University of Southern California Keck School of Medicine, Los Angeles, and Providence Saint John's Health Center, Santa Monica.
Orthopedic Physicians Alaska, Anchorage.
ACR Open Rheumatol. 2025 Jan;7(1):e11789. doi: 10.1002/acr2.11789.
Patients with uncontrolled gout have few treatment options. Pegloticase lowers serum urate (SU) levels, but antidrug antibodies limit SU-lowering response and increase infusion reaction (IR) risk. Methotrexate (MTX) cotherapy increases pegloticase response rates and lowers IR risk in pegloticase-naïve patients. Therefore, the question of re-treating patients with previous pegloticase monotherapy failure has arisen. The ADVANCE open-label trial examined pegloticase plus MTX cotherapy efficacy and safety following pegloticase monotherapy failure.
Patients with uncontrolled gout (SU levels ≥6 mg/dL, oral urate-lowering therapy failure or intolerance, and ≥1 gout sign or symptom) who previously lost SU-lowering response to pegloticase monotherapy were included. Key exclusion criteria were moderate-to-severe IR or anaphylaxis to pegloticase, MTX contraindication, immunosuppressant administration, glucose-6-phosphate dehydrogenase deficiency, and estimated glomerular filtration rate <30 mL/min/1.73m. After a 6-week subcutaneous MTX run-in (at 25 mg/wk), patients entered 24-week pegloticase (at 8 mg biweekly) plus MTX treatment. The primary end point was SU-lowering response rate during month 6 (SU levels <6 mg/dL for ≥80% of weeks 20-24). Safety was assessed via adverse events (AEs) and laboratory monitoring.
Eleven patients began pegloticase plus MTX treatment (91% male patients, mean age 58.6 ± 11.3 years, mean ± SD SU levels 8.5 ± 3.2 mg/dL, 91% tophaceous). Previous pegloticase course was 2 to 27 infusions, with the last infusion admins being a mean ± SD of 3.7 ± 2.4 years before. One patient (9%) maintained response during month 6; 10 patients prematurely discontinued treatment (loss of SU lowering [n = 8], IR [n = 2]). Eight patients (73%) experienced ≥1 AE, most commonly gout flare. All AEs were mild or moderate.
Pegloticase plus MTX response rate following failed monotherapy was lower (9% vs 71%) and IR rate was higher (18% vs 4%) than in pegloticase-naïve patients. These findings demonstrate the challenge of overcoming established antipegloticase antibodies and emphasize the importance of initiating immunomodulation before the first pegloticase exposure.
痛风控制不佳的患者治疗选择有限。聚乙二醇化尿酸酶可降低血清尿酸（SU）水平，但抗药抗体限制了SU降低反应并增加了输注反应（IR）风险。甲氨蝶呤（MTX）联合治疗可提高聚乙二醇化尿酸酶初治患者的反应率并降低IR风险。因此，对于之前聚乙二醇化尿酸酶单药治疗失败的患者是否重新治疗的问题随之而来。ADVANCE开放标签试验研究了聚乙二醇化尿酸酶单药治疗失败后聚乙二醇化尿酸酶联合MTX治疗的疗效和安全性。
纳入痛风控制不佳（SU水平≥6mg/dL，口服降尿酸治疗失败或不耐受，且有≥1个痛风体征或症状）且之前对聚乙二醇化尿酸酶单药治疗失去SU降低反应的患者。主要排除标准为对聚乙二醇化尿酸酶有中度至重度IR或过敏反应、MTX禁忌、使用免疫抑制剂、葡萄糖-6-磷酸脱氢酶缺乏以及估计肾小球滤过率<30mL/min/1.73m²。经过6周的皮下MTX导入期（25mg/周）后，患者进入24周的聚乙二醇化尿酸酶（每两周8mg）联合MTX治疗。主要终点是第6个月时的SU降低反应率（第20 - 24周中≥80%的周SU水平<6mg/dL）。通过不良事件（AE）和实验室监测评估安全性。
11名患者开始聚乙二醇化尿酸酶联合MTX治疗（91%为男性患者，平均年龄58.6±11.3岁，平均±标准差SU水平8.5±3.2mg/dL，91%有痛风石）。之前的聚乙二醇化尿酸酶疗程为2至27次输注，最后一次输注平均±标准差为3.7±2.4年前。1名患者（9%）在第6个月维持反应；10名患者提前终止治疗（SU降低丧失[n = 8]，IR[n = 2]）。8名患者（73%）经历≥1次AE，最常见的是痛风发作。所有AE均为轻度或中度。
与聚乙二醇化尿酸酶初治患者相比，单药治疗失败后聚乙二醇化尿酸酶联合MTX的反应率更低（9%对71%），IR率更高（18%对4%）。这些发现表明克服已形成的抗聚乙二醇化尿酸酶抗体具有挑战性，并强调在首次接触聚乙二醇化尿酸酶之前启动免疫调节的重要性。
