Hasni Sarfaraz, Temesgen-Oyelakin Yenealem, Davis Michael, Chu Jun, Poncio Elaine, Naqi Mohammad, Gupta Sarthak, Wang Xinghao, Oliveira Christopher, Claybaugh Dillon, Dey Amit, Lu Shajia, Carlucci Philip, Purmalek Monica, Manna Zerai G, Shi Yinghui, Ochoa-Navas Isabel, Chen Jinguo, Mukherjee Amrita, Han Kyu Lee, Cheung Foo, Koroleva Galina, Belkaid Yasmine, Tsang John S, Apps Richard, Thomas Donald E, Heller Theo, Gadina Massimo, Playford Martin P, Li Xiaobai, Mehta Nehal N, Kaplan Mariana J
Lupus Clinical Trials Unit, Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
Lupus Clinical Trials Unit, Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Ann Rheum Dis. 2022 Oct 12;81(11):1576-1584. doi: 10.1136/ard-2022-222658.
Premature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE.
Eighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed.
Seventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose.
PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE.
NCT02338999.
系统性红斑狼疮（SLE）患者的过早心血管事件会导致发病和死亡，迄今为止尚无有效的预防策略。免疫失调和代谢紊乱似乎在SLE血管疾病的诱发中起重要作用。过氧化物酶体增殖物激活受体γ激动剂吡格列酮（PGZ）可抑制小鼠狼疮中的血管损伤和免疫失调，并改善其他炎症性疾病中的内皮功能障碍。我们假设PGZ可以改善SLE患者的血管功能障碍和心脏代谢参数。
80例轻至重度疾病活动的SLE患者被随机分为接受PGZ治疗3个月后再接受安慰剂治疗，或反之，采用双盲、交叉设计，洗脱期为2个月。主要终点是通过多模式评估测量的内皮功能和动脉炎症参数。还进行了疾病活动、中性粒细胞失调、代谢紊乱和基因表达研究的其他结局指标评估。
72例患者完成了研究。与安慰剂相比，PGZ与心脏-踝血管指数（一种动脉僵硬度测量指标）的显著降低相关。PGZ可改善各种代谢参数，包括胰岛素抵抗和脂蛋白谱。与安慰剂相比，PGZ治疗时循环中性粒细胞胞外诱捕水平也显著降低。服用PGZ时经历的大多数不良事件较轻，减少PGZ剂量后可缓解。
PGZ耐受性良好，可显著改善SLE患者的血管僵硬度和心脏代谢参数。结果表明，PGZ应作为SLE心血管疾病风险调节剂进行进一步研究。
NCT02338999。
