Wanner Christoph, Feldt-Rasmussen Ulla, Jovanovic Ana, Linhart Aleš, Yang Meng, Ponce Elvira, Brand Eva, Germain Dominique P, Hughes Derralynn A, Jefferies John L, Martins Ana Maria, Nowak Albina, Vujkovac Bojan, Weidemann Frank, West Michael L, Ortiz Alberto
Department of Medicine, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany.
Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
ESC Heart Fail. 2020 Jun;7(3):825-834. doi: 10.1002/ehf2.12647. Epub 2020 Feb 26.
Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.
Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = -0.41 [-0.68, -0.15] mm/year, P <0.01; IVST: n = 38, slope difference = -0.32 [-0.67, 0.02] mm/year, P = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m /year, P = 0.80).
Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.
由于表型异质性和缺乏合适的对照组，设计针对大量女性法布里病患者群体的长期治疗效果研究具有挑战性，且尚未见相关报道。我们比较了阿加糖酶β治疗后的长期心肌病和肾功能结果与之前未接受过治疗时的结果。
自我对照的治疗前和治疗后比较（分段混合线性模型）纳入了开始治疗时年龄≥18岁、接受阿加糖酶β（每两周0.9 - 1.1 mg/kg）治疗≥2年、在10年随访期间有≥2次治疗前和≥2次治疗后结果测量的法布里病女性患者。左心室后壁厚度（LVPWT）/室间隔厚度（IVST）和估计肾小球滤过率（eGFR，慢性肾脏病流行病学协作组肌酐方程）分析分别纳入了42例和86例患者，开始治疗时年龄分别为50.0岁和46.3岁。LVPWT和IVST在治疗前随访期间增加（随访3.5年），但在3.6年的治疗期间稳定（LVPWT：n = 38，斜率差异[95%置信区间（CI）]= -0.41[-0.68，-0.15]mm/年，P<0.01；IVST：n = 38，斜率差异= -0.32[-0.67，0.02]mm/年，P = 0.07）。这些结果不受肾脏受累情况或抗蛋白尿药物使用的影响。与未接受治疗期间（随访3.6年）相比，eGFR下降仍然较小，并在4.1年的治疗期间稳定在正常范围内（斜率差异，95%CI：-0.13[-1.15，0.89]mL/min/1.73m²/年，P = 0.80）。
在治疗前随访期间进展的心脏肥大，在持续的阿加糖酶β治疗期间似乎稳定下来。eGFR下降仍在正常范围内。这表明治疗可能预防女性患者法布里病相关的心肌病进一步进展，并维持正常肾功能。
