Yu Christine, Chopra Inder J, Ha Edward
Department of Medicine, University of California , Los Angeles, Los Angeles, California, 90095 , USA.
Division of Endocrinology, Department of Medicine, University of California , 757 Westwood Plaza Blvd, Suite 7501, Los Angeles, CA, 90095 , USA.
Endocrinol Diabetes Metab Case Rep. 2015;2015:140092. doi: 10.1530/EDM-14-0092. Epub 2015 Feb 1.
Ipilimumab, a novel therapy for metastatic melanoma, inhibits cytotoxic T-lymphocyte apoptosis, causing both antitumor activity and significant autoimmunity, including autoimmune thyroiditis. Steroids are frequently used in treatment of immune-related adverse events; however, a concern regarding the property of steroids to reduce therapeutic antitumor response exists. This study describes the first reported case of ipilimumab-associated thyroid storm and implicates iopanoic acid as an alternative therapy for immune-mediated adverse effects. An 88-year-old woman with metastatic melanoma presented with fatigue, anorexia, decreased functional status, and intermittent diarrhea for several months, shortly after initiation of ipilimumab - a recombinant human monoclonal antibody to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). On arrival, she was febrile, tachycardic, and hypertensive with a wide pulse pressure, yet non-toxic appearing. She had diffuse, non-tender thyromegaly. An electrocardiogram (EKG) revealed supraventricular tachycardia. Blood, urine, and stool cultures were collected, and empiric antibiotics were started. A computed tomography (CT) angiogram of the chest was negative for pulmonary embolism or pneumonia, but confirmed a diffusely enlarged thyroid gland, which prompted thyroid function testing. TSH was decreased at 0.16 μIU/ml (normal 0.3-4.7); free tri-iodothyronine (T3) was markedly elevated at 1031 pg/dl (normal 249-405), as was free thyroxine (T4) at 5.6 ng/dl (normal 0.8-1.6). With iopanoic acid and methimazole therapy, she markedly improved within 48 h, which could be attributed to lowering of serum T3 with iopanoic acid rather than to any effect of the methimazole. Ipilimumab is a cause of overt thyrotoxicosis and its immune-mediated adverse effects can be treated with iopanoic acid, a potent inhibitor of T4-to-T3 conversion.
While ipilimumab more commonly causes autoimmune thyroiditis, it can also cause thyroid storm and clinicians should include thyroid storm in their differential diagnosis for patients who present with systemic inflammatory response syndrome.Immune-related adverse reactions usually occur after 1-3 months of ipilimumab and baseline thyroid function testing should be completed before initiation with ipilimumab.Conflicting data exist on the use of prednisone for treatment of CTLA4 adverse effects and its attenuation of ipilimumab's antitumor effect. Iopanoic acid may be considered as an alternative therapy in this setting.
伊匹单抗是一种用于转移性黑色素瘤的新型疗法，可抑制细胞毒性T淋巴细胞凋亡，从而产生抗肿瘤活性并引发显著的自身免疫反应，包括自身免疫性甲状腺炎。类固醇常用于治疗免疫相关不良事件；然而，人们担心类固醇会降低治疗性抗肿瘤反应。本研究描述了首例报道的伊匹单抗相关甲状腺风暴病例，并表明碘番酸可作为免疫介导不良反应的替代疗法。一名88岁的转移性黑色素瘤女性患者，在开始使用伊匹单抗（一种针对细胞毒性T淋巴细胞相关抗原4（CTLA4）的重组人单克隆抗体）后不久，出现疲劳、厌食、功能状态下降和间歇性腹泻数月。入院时，她发热、心动过速且高血压，脉压宽，但无中毒表现。她有弥漫性、无压痛的甲状腺肿大。心电图（EKG）显示室上性心动过速。采集了血液、尿液和粪便培养物，并开始使用经验性抗生素。胸部计算机断层扫描（CT）血管造影显示无肺栓塞或肺炎，但证实甲状腺弥漫性肿大，这促使进行甲状腺功能测试。促甲状腺激素（TSH）降至0.16μIU/ml（正常范围0.3 - 4.7）；游离三碘甲状腺原氨酸（T3）显著升高至1031pg/dl（正常范围249 - 405），游离甲状腺素（T4）为5.6ng/dl（正常范围0.8 - 1.6）。使用碘番酸和甲巯咪唑治疗后，她在48小时内明显好转，这可能归因于碘番酸降低了血清T3，而非甲巯咪唑发挥了任何作用。伊匹单抗可导致明显的甲状腺毒症，其免疫介导的不良反应可用碘番酸治疗，碘番酸是一种有效的T4向T3转化抑制剂。
虽然伊匹单抗更常见的是引起自身免疫性甲状腺炎，但它也可导致甲状腺风暴，临床医生在对出现全身炎症反应综合征的患者进行鉴别诊断时应考虑甲状腺风暴。免疫相关不良反应通常在使用伊匹单抗1 - 3个月后出现，在开始使用伊匹单抗前应完成基线甲状腺功能测试。关于泼尼松用于治疗CTLA4不良反应及其对伊匹单抗抗肿瘤作用的减弱存在相互矛盾的数据。在这种情况下，可考虑将碘番酸作为替代疗法。
