Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, United States.
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, United States.
Front Immunol. 2020 May 21;11:1000. doi: 10.3389/fimmu.2020.01000. eCollection 2020.
A 3.5 year old Hispanic female presented with signs and symptoms concerning for MPS II (Hunter Syndrome). The diagnosis of MPS II was confirmed by enzyme and molecular testing. Genetic evaluation revealed undetectable plasma iduronate-2-sulfatase enzyme activity and an inversion between intron 7 of the gene and a region near exon 3 of . This inversion is the molecular cause for ~8% of cases of MPS II and often results in a severe phenotype. X-inactivation studies revealed an inactivation ratio of 100:0. Given the patient's undetectable enzyme level, in combination with a severe IDS gene mutation, classic features at time of presentation, and the significantly skewed X inactivation, there was concern that she was at high risk of developing high and sustained antibody titers to idursulfase which would limit her benefit from enzyme replacement therapy (ERT). Anti-drug neutralizing antibodies to idursulfase have been associated with reduced systemic exposure to idursulfase and poorer clinical outcomes. Therefore, the decision was made to concurrently treat the patient with immune tolerance induction therapy during the first month of treatment with idursulfase in order to decrease the risk of developing high sustained antibody titers. The immune tolerance induction protocol consisted of rituximab weekly for 4 weeks, methotrexate three times a week for 3 weeks and monthly IVIG through B-cell and immunoglobulin recovery. Immune tolerance induction was initiated concurrently with the start of ERT. The patient had no significant adverse effects related to undergoing immune tolerance induction therapy and two and half years later is doing well with significantly reduced urine glycosaminoglycans and very low anti-drug antibody titers. This immune tolerance induction protocol could be considered for other patients with MPS II as well as patients with other lysosomal storage disorders who are starting on enzyme replacement therapy and are at high risk of developing neutralizing anti-drug antibodies.
一位 3.5 岁的西班牙裔女性出现了疑似 MPS II（亨特综合征）的症状和体征。MPS II 的诊断通过酶和分子检测得到确认。基因评估显示，血浆艾杜糖-2-硫酸酯酶活性无法检测到， 基因第 7 内含子与第 3 外显子附近区域之间发生了倒位。这种倒位是约 8%的 MPS II 病例的分子原因，通常导致严重的表型。X 染色体失活研究显示失活比为 100:0。鉴于患者的酶水平无法检测到，加上严重的 IDS 基因突变、发病时的典型特征以及明显偏斜的 X 染色体失活，人们担心她有很高的风险产生针对艾杜硫酸酶的高且持续的抗体滴度，从而限制她从酶替代疗法（ERT）中获益。针对艾杜硫酸酶的抗药物中和抗体与艾杜硫酸酶的系统暴露减少和较差的临床结局有关。因此，决定在开始 ERT 的第一个月同时对患者进行免疫耐受诱导治疗，以降低产生高持续抗体滴度的风险。免疫耐受诱导方案包括每周用利妥昔单抗治疗 4 周、每周用甲氨蝶呤治疗 3 周和每月静脉注射免疫球蛋白以恢复 B 细胞和免疫球蛋白。免疫耐受诱导与 ERT 的开始同时进行。患者在接受免疫耐受诱导治疗方面没有出现明显的不良反应，两年半后，她的病情良好，尿液糖胺聚糖显著减少，抗药物抗体滴度非常低。该免疫耐受诱导方案可考虑用于其他 MPS II 患者以及开始接受酶替代治疗且有产生中和抗药物抗体高风险的其他溶酶体贮积症患者。
