Mhanni Aizeddin A, Auray-Blais Christiane, Boutin Michel, Johnston Alie, LeMoine Kaye, Patterson Jill, Aerts Johannes M F G, West Michael L, Rockman-Greenberg Cheryl
Department of Pediatrics and Child Health, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
Mol Genet Metab Rep. 2020 Jun 24;24:100618. doi: 10.1016/j.ymgmr.2020.100618. eCollection 2020 Sep.
Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb deletion, not amenable to chaperone therapy, leading to profound reduction in α-galactosidase A (α-gal A) enzyme activity. Over a 3-year period of ERT, increasing IgG antibody titres against α-gal A were noted. After starting ERT serial urine globotriaosylceramide (Gb) measurements showed an upward trend from 333 to 2260 μg/mmol creatinine for patient 1 and 1165 to 2260 μg/mmol creatinine for patient 2. Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb analogues were also found. The patients experienced recurrent infusion-associated reactions necessitating premedication and prolonged infusion times. Over the 3-year period of ERT, the patients experienced continued malaise, gastrointestinal symptoms and neuropathic pain. In addition, they had increasing anxiety related to their disease and apparent lack of response to ERT which led to a decision to ultimately stop ERT. No other approved treatment options are currently available for these patients. It is possible that the rapid development of the high antidrug neutralizing antibody (ADA) titres is related to the large deletion leading to virtually absent enzyme activity. It remains unclear if their symptomatology during the period of receiving ERT is related to lack of its efficacy, the rising ADA titres, or both. These two patients highlight the need for further research into the management of antidrug antibodies and additional therapeutic approaches for FD.
The development of very high antidrug antibody titres in response to ERT in two related adolescent males with FD highlight the need for other therapeutic options for patients in whom ERT or other currently approved therapies does not meet their treatment needs.
酶替代疗法（ERT）已被证明可稳定法布里病（FD）的某些方面。然而，在一些接受ERT治疗的患者中，已记录到高抗体滴度，全身表现的临床改善有限，且常伴有明显的药物不良反应。我们报告了两名相关的青少年男性，他们存在一个4.5 kb的缺失，无法进行伴侣疗法，导致α - 半乳糖苷酶A（α - gal A）酶活性显著降低。在ERT治疗的3年期间，发现针对α - gal A的IgG抗体滴度不断升高。开始ERT治疗后，连续尿球三糖神经酰胺（Gb）测量显示，患者1从333 μg/mmol肌酐上升至2260 μg/mmol肌酐，患者2从1165 μg/mmol肌酐上升至2260 μg/mmol肌酐，呈上升趋势。还发现尿液和血浆中球三糖鞘氨醇（溶酶体 - Gb类似物）水平显著升高。患者经历了反复的输液相关反应，需要进行预处理并延长输液时间。在ERT治疗的3年期间，患者持续感到不适、出现胃肠道症状和神经性疼痛。此外，他们对疾病的焦虑增加，且对ERT明显缺乏反应，最终决定停止ERT。目前这些患者没有其他获批的治疗选择。高抗药中和抗体（ADA）滴度的快速发展可能与导致几乎没有酶活性的大片段缺失有关。在接受ERT治疗期间他们的症状是与缺乏疗效、ADA滴度上升还是两者都有关仍不清楚。这两名患者凸显了对FD患者抗药抗体管理和其他治疗方法进行进一步研究的必要性。
两名患有FD的相关青少年男性在接受ERT治疗时出现非常高的抗药抗体滴度，这凸显了对于ERT或其他当前获批疗法无法满足其治疗需求的患者需要其他治疗选择。
