Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia
Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia
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DOI：
10.1001/jamanetworkopen.2018.4169
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发表时间：
2018-11-01
影响因子：
13.8
通讯作者：
Walter, Jolan
中科院分区：
文献类型：
--
作者：
Barmettler, Sara;Ong, Mei-Sing;Walter, Jolan
利妥昔单抗是一种抗CD 20嵌合抗体，用于各种临床适应症。在利妥昔单抗治疗前后，还没有广泛采用一致的免疫监测。然而，也有一部分患者在利妥昔单抗治疗后出现长期的、有症状的低丙种球蛋白血症，在利妥昔单抗治疗前后进行监测有助于识别这些患者，并采取措施防止过度的发病率和死亡率。（特别是，低免疫球蛋白G），与低丙种球蛋白血症相关的感染风险，以及与死亡风险增加相关的变量。和参与者一项队列研究于1997年1月1日至2017年12月31日在一家大型三级转诊中心（Partners HealthCare System）对8633名接受利妥昔单抗的患者进行了队列研究。暴露利妥昔单抗给药。主要结局和指标主要结局指标是免疫球蛋白测量、感染并发症和死亡率。考克斯回归分析被用来检查结果感染并发症的生存，调整年龄，性别，并适应利妥昔单抗use.Results的8633例患者接受利妥昔单抗在大型，学术，卫生保健系统，4479满足纳入标准，平均（SD）年龄为59.8（16.2）岁，2280例（50.9%）是女性。大多数患者（3824例[85.4%]）在利妥昔单抗治疗前未检查免疫球蛋白水平。在那些有水平测定的患者中，313例（47.8%）患者在开始利妥昔单抗治疗前出现低丙种球蛋白血症。利妥昔单抗给药后，观察到低丙种球蛋白血症恶化。在研究队列中，使用利妥昔单抗后严重感染的发生率增加（从17.2%增加到21.7%; P <0.001）。在生存分析中，死亡率的增加与年龄的增加有关（风险比[HR]，1.02; 95% CI，1.01-1.02; P < .001），男性（HR，1.14; 95% CI，1.02-1.28; P = 0.02），以及治疗前6个月的严重感染并发症（HR，3.14; 95%CI，2.77-3.55; P < .001）和在第一次利妥昔单抗输注之后（HR，4.97; 95%CI，4.41-5.60; P < .001）。共201名患者（4.5%）在利妥昔单抗治疗后接受免疫球蛋白替代治疗，在这些患者中，较高的免疫球蛋白替代累积剂量与严重感染并发症风险降低相关（HR，0.98; 95% CI，0.96-0.99;结论和相关性许多患者在利妥昔单抗给药前后都没有被筛查或正确鉴定为低丙种球蛋白血症。在利妥昔单抗治疗之前和之后监测免疫球蛋白水平可以允许更早地识别发生显著感染的风险，并识别可能受益于免疫球蛋白替代的患者，这反过来可能有助于避免过度的发病率和死亡率。
IMPORTANCE Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality.OBJECTIVE To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality.DESIGN, SETTING, AND PARTICIPANTS A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017 at a large, tertiary referral center (Partners HealthCare System).EXPOSURES Rituximab administration.MAIN OUTCOMES AND MEASURES The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use.RESULTS Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P < .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P < .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P < .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002).CONCLUSIONS AND RELEVANCE Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.