Orthopedic Physicians Alaska, 3801 Lake Otis Parkway, Suite 300, Anchorage, AK, 99508, USA.
Arizona Arthritis & Rheumatology Associates, 4550 East Bell Road, Phoenix, AZ, 85032, USA.
Arthritis Res Ther. 2022 Aug 25;24(1):208. doi: 10.1186/s13075-022-02865-z.
Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase + methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here.
Uncontrolled gout patients (serum urate [SU] ≥ 6 mg/dL and SU ≥ 6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4 weeks before and during pegloticase therapy. Twelve-month responder rate (SU < 6 mg/dL for ≥ 80% during month 12), 52-week change from baseline in SU, and extended safety were examined. Efficacy analyses were performed for patients receiving ≥ 1 pegloticase infusion. Pharmacokinetics (PK)/anti-drug antibodies (ADAs) were examined and related to efficacy/safety findings.
Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4-year gout history, pre-therapy SU 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24 weeks, one patient exited the study per protocol at 24 weeks (enrolled prior to treatment extension amendment), and 10 remained in the study through week 52. Of the 10, 8 completed 52 weeks of pegloticase + methotrexate and were 12-month responders. The remaining two discontinued pegloticase + methotrexate at week 24 (met treatment goals) and stayed in the study under observation (allopurinol prescribed at physicians' discretion); one remained a responder at 12 months. At 52 weeks, change from baseline in SU was - 8.2 ± 4.1 mg/dL (SU 1.1 ± 2.4 mg/dL, n = 10). Gout flares were common early in treatment but progressively decreased while on therapy (weeks 1-12, 13/14 [92.9%]; weeks 36-52, 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titers; fewer patients had trough concentrations (C) below the quantitation limit (BQL), and the median C was higher (1.03 µg/mL vs. BQL) than pegloticase monotherapy trials.
Pegloticase + methotrexate co-therapy was well-tolerated over 12 months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates.
ClinicalTrials.gov, NCT03635957 . Registered on 17 August 2018.
文献表明免疫调节联合治疗可提高接受培戈洛酶治疗的未控制/难治性痛风患者的应答率。MIRROR 开放性试验显示，培戈洛酶联合甲氨蝶呤治疗的 6 个月应答率为 79%，而培戈洛酶单药治疗的应答率为 42%。本文介绍了更长时间的疗效/安全性数据。
纳入未控制的痛风患者（血清尿酸 [SU]≥6mg/dL，且尽管接受了降尿酸治疗 [ULT]，ULT 不耐受或功能受限的痛风石，SU 仍≥6mg/dL）。排除免疫功能低下、G6PD 缺乏、严重肾脏疾病或甲氨蝶呤禁忌的患者。口服甲氨蝶呤（15mg/周）和叶酸（1mg/天）在培戈洛酶治疗前 4 周和治疗期间给予。12 个月应答率（SU<6mg/dL，第 12 个月期间≥80%）、SU 从基线的 52 周变化和延长的安全性进行了检查。对接受≥1 次培戈洛酶输注的患者进行了疗效分析。检查了药代动力学（PK）/抗药物抗体（ADA），并将其与疗效/安全性发现相关联。
纳入了 14 名患者（均为男性，49.3±8.7 岁，痛风病史 13.8±7.4 年，治疗前 SU 9.2±2.5mg/dL）。有 3 名患者无应答，并在 24 周前停止了研究治疗，1 名患者在 24 周时根据方案退出了研究（在治疗扩展修正案之前入组），10 名患者在第 52 周时仍在研究中。在这 10 名患者中，有 8 名完成了 52 周的培戈洛酶联合甲氨蝶呤治疗，是 12 个月的应答者。其余 2 名患者在第 24 周时停止了培戈洛酶联合甲氨蝶呤治疗（达到了治疗目标），并在观察下继续留在研究中（医生酌情开具别嘌醇）；其中 1 名患者在 12 个月时仍有应答。第 52 周时，SU 从基线的变化为-8.2±4.1mg/dL（SU 1.1±2.4mg/dL，n=10）。痛风发作在治疗早期很常见，但随着治疗的进行逐渐减少（第 1-12 周，14/14 [92.9%]；第 36-52 周，8/8 [25.0%]）。1 名患者从败血症中恢复（严重不良事件）。有 2 名无应答者产生了高 ADA 滴度；较少的患者有低于定量下限（BQL）的谷浓度（C），中位数 C 较高（1.03μg/mL，高于 BQL），与培戈洛酶单药治疗试验相比。
培戈洛酶联合甲氨蝶呤治疗在 12 个月内耐受性良好，SU 持续降低，痛风发作逐渐减少，无新的安全性问题。抗体/PK 结果表明甲氨蝶呤可减轻 ADA 的形成，同时应答率也更高。
ClinicalTrials.gov，NCT03635957。于 2018 年 8 月 17 日注册。
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