Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, 92093, USA.
Drugs. 2023 Nov;83(16):1501-1521. doi: 10.1007/s40265-023-01944-y. Epub 2023 Oct 11.
Hyperuricemia with consequent monosodium urate crystal deposition leads to gout, characterized by painful, incapacitating inflammatory arthritis flares that are also associated with increased cardiovascular event and related mortality risk. This narrative review focuses on emerging pharmacologic urate-lowering treatment (ULT) and management strategies in gout. Undertreated, gout can progress to palpable tophi and joint damage. In oral ULT clinical trials, target serum urate of < 6.0 mg/dL can be achieved in ~ 80-90% of subjects, with flare burden reduction by 1-2 years. However, real-world ULT results are far less successful, due to both singular patient nonadherence and prescriber undertreatment, particularly in primary care, where most patients are managed. Multiple dose titrations commonly needed to optimize first-line allopurinol ULT monotherapy, and substantial potential toxicities and other limitations of approved, marketed oral monotherapy ULT drugs, promote hyperuricemia undertreatment. Common gout comorbidities with associated increased mortality (e.g., moderate-severe chronic kidney disease [CKD], type 2 diabetes, hypertension, atherosclerosis, heart failure) heighten ULT treatment complexity and emphasize unmet needs for better and more rapid clinically significant outcomes, including attenuated gout flare burden. The gout drug armamentarium will be expanded by integrating sodium-glucose cotransporter-2 (SGLT2) inhibitors with uricosuric and anti-inflammatory properties as well as clinically indicated antidiabetic, nephroprotective, and/or cardioprotective effects. The broad ULT developmental pipeline is loaded with multiple uricosurics that selectively target uric acid transporter 1 (URAT1). Evolving ULT approaches include administering selected gut anaerobic purine degrading bacteria (PDB), modulating intestinal urate transport, and employing liver-targeted xanthine oxidoreductase mRNA knockdown. Last, emerging measures to decrease the immunogenicity of systemically administered recombinant uricases should simplify treatment regimens and further improve outcomes in managing the most severe gout phenotypes.
高尿酸血症导致单钠尿酸盐晶体沉积，进而引发痛风，其特征是疼痛、使人丧失能力的炎症性关节炎发作，同时也与心血管事件和相关死亡风险增加有关。本综述重点介绍痛风新兴的降尿酸治疗（ULT）和管理策略。如果治疗不充分，痛风可能会发展为可触及的痛风石和关节损伤。在口服 ULT 临床试验中，约 80-90%的受试者可以达到血清尿酸目标值 < 6.0 mg/dL，并且在 1-2 年内减少发作负担。然而，由于患者个体不遵医嘱和医生治疗不足，实际 ULT 结果远不如预期，特别是在大多数患者接受管理的初级保健中。为了优化一线别嘌醇 ULT 单药治疗，通常需要进行多次剂量滴定，而且已批准上市的口服单药 ULT 药物存在大量潜在毒性和其他限制，这也促进了高尿酸血症治疗不足。常见的痛风合并症（如中度至重度慢性肾脏病[CKD]、2 型糖尿病、高血压、动脉粥样硬化、心力衰竭）增加了 ULT 治疗的复杂性，并强调需要更好、更快的具有临床意义的治疗结果，包括减轻痛风发作负担。将具有钠-葡萄糖共转运蛋白-2（SGLT2）抑制剂和尿酸排泄及抗炎特性，以及具有临床指征的抗糖尿病、肾脏保护和/或心脏保护作用的药物纳入痛风药物治疗领域，将扩大痛风药物治疗的范围。具有选择性靶向尿酸转运蛋白 1（URAT1）的多种新型尿酸排泄剂正在广泛开发中。不断发展的 ULT 方法包括使用选定的肠道厌氧嘌呤降解细菌（PDB）、调节肠道尿酸转运以及采用肝靶向黄嘌呤氧化酶 mRNA 敲低。最后，降低系统给予重组尿酸酶的免疫原性的新方法应能简化治疗方案，并进一步改善治疗最严重痛风表型的疗效。
