IgG Fc galactosylation predicts response to methotrexate in early rheumatoid arthritis
IgG Fc galactosylation predicts response to methotrexate in early rheumatoid arthritis
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DOI：
10.1186/s13075-017-1389-7
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发表时间：
2017-08-09
影响因子：
4.9
通讯作者：
Catrina, Anca I.
中科院分区：
文献类型：
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作者：
Lundstrom, Susanna L.;Hensvold, Aase H.;Catrina, Anca I.
背景资料：甲氨蝶呤（MTX）是类风湿关节炎（RA）的标准一线治疗药物，临床疗效多变，难以预测。免疫球蛋白G（IgG）的糖基化状态在RA中改变，并受到MTX治疗的影响。我们的目的是进一步调查，如果IgG糖基化在未经治疗的早期RA可以预测治疗反应MTX.Methods：我们使用了鸟枪蛋白质组学的方法来筛选的Fc糖肽在血清中的12个对照组和59个未经治疗的早期RA患者之前和之后的MTX启动。根据欧洲抗风湿联盟，在治疗开始后中位数14周（范围13-15）时定义MTX治疗反应。血清阳性患者定义为基线时抗瓜氨酸蛋白抗体和/或类风湿因子检测阳性的患者（n = 44）。使用单变量和多变量统计进行数据分析。结果如下：我们可以证实，与MTX治疗后部分恢复的对照组相比，未治疗的早期RA患者的半乳糖基化聚糖丰度较低。这在未来的无应答者中比在MTX治疗应答者中更明显，结果通过基线Fc聚糖、蛋白质组学和临床数据的多变量统计分析进一步验证和证实。我们发现，IgG 1的主要无半乳糖基化（FA 2）与主要单半乳糖基化和双半乳糖基化Fc聚糖（FA 2G 1和FA 2G 2）之间的比率是区分应答者与非应答者的最突出因素。低基线FA 2/[FA 2G 1 + FA 2G 2]-IgG 1比值与无应答相关（OR 5.3 [1.6-17.0]），能够区分未来的无应答者和MTX治疗应答者，灵敏度为70%（95%CI 46-88%），特异性为69%（95%CI 52-83%）。对于血清阳性患者（n = 44），这一趋势得到改善，灵敏度为73%（95% CI 45-92%），特异性为79%（95% CI 60-92%）。我们证明了FA 2/[FA 2G 1 + FA 2G 2] IgG 1是一种与MTX无应答患者显著相关的候选生物标志物，对MTX临床应答的预测具有潜在价值。
Background: Methotrexate (MTX) is the standard first-line therapy in rheumatoid arthritis (RA) with variable clinical efficacy that is difficult to predict. The glycosylation status of immunoglobulin G (IgG) is altered in RA and influenced by MTX treatment. We aimed to further investigate if IgG glycosylation in untreated early RA can predict therapeutic response to MTX.Methods: We used a shotgun proteomic approach to screen for the Fc glycopeptides in the serum of 12 control subjects and 59 untreated patients with early RA prior to and following MTX initiation. MTX treatment response was defined according to the European League Against Rheumatism at a median of 14 weeks (range 13-15) after treatment initiation. Seropositive patients were defined as those testing positive for anticitrullinated protein antibodies and/or rheumatoid factor at baseline (n = 44). Data analysis was performed using uni-and multivariate statistics. Results: We could confirm a low abundance of galactosylated glycans in untreated patients with early RA compared with control subjects that was partially restored by MTX treatment. This was more evident among future nonresponders than among responders to MTX treatment.Results were further validated and confirmed by multivariate statistical analysis of the baseline Fc glycan, proteomic, and clinical data. We found that the ratio between the main agalactosylated (FA2) and main mono-and di-galactosylated Fc glycans (FA2G1 and FA2G2) of IgG1 ranked as the most prominent factor distinguishing responders from nonresponders. A low baseline ratio of FA2/[ FA2G1 + FA2G2]-IgG1 was associated with nonresponse (OR 5.3 [1.6-17.0]) and was able to discriminate future nonresponders from responders to MTX therapy with a sensitivity of 70% (95% CI 46-88%) and a specificity of 69% (95% CI 52-83%). For seropositive patients (n = 44), this trend was improved with a sensitivity of 73% (95% CI 45-92%) for nonresponse and a specificity of 79% (95% CI 60-92%).Conclusions: We show that the FA2/[ FA2G1 + FA2G2] of IgG1 is a biomarker candidate that is significantly associated with nonresponding patients and has potential value for prediction of MTX clinical response.