Lundström Susanna L, Hensvold Aase H, Rutishauser Dorothea, Klareskog Lars, Ytterberg A Jimmy, Zubarev Roman A, Catrina Anca I
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheelesväg 2, SE 17177, Stockholm, Sweden.
Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Arthritis Res Ther. 2017 Aug 9;19(1):182. doi: 10.1186/s13075-017-1389-7.
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.
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.
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%).
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.
甲氨蝶呤（MTX）是类风湿关节炎（RA）的标准一线治疗药物，但其临床疗效不一，难以预测。RA患者免疫球蛋白G（IgG）的糖基化状态发生改变，且受MTX治疗影响。我们旨在进一步研究未经治疗的早期RA患者的IgG糖基化是否能预测对MTX的治疗反应。
我们采用鸟枪法蛋白质组学方法，对12名对照受试者和59名未经治疗的早期RA患者在开始MTX治疗前后的血清中的Fc糖肽进行筛选。MTX治疗反应根据欧洲抗风湿病联盟的标准，在治疗开始后中位14周（范围13 - 15周）时确定。血清阳性患者定义为基线时抗瓜氨酸化蛋白抗体和/或类风湿因子检测呈阳性的患者（n = 44）。使用单变量和多变量统计进行数据分析。
我们可以证实，与对照受试者相比，未经治疗的早期RA患者中半乳糖基化聚糖的丰度较低，MTX治疗可部分恢复。这在未来无反应者中比在MTX治疗反应者中更明显。通过对基线Fc聚糖、蛋白质组学和临床数据的多变量统计分析，结果得到进一步验证和确认。我们发现，IgG1的主要非半乳糖基化（FA2）与主要单半乳糖基化和双半乳糖基化Fc聚糖（FA2G1和FA2G2）之间的比率是区分反应者与无反应者的最显著因素。FA2/[FA2G1 + FA2G2]-IgG1的低基线比率与无反应相关（比值比5.3 [1.6 - 17.0]），能够以70%（95%置信区间46 - 88%）的敏感性和69%（95%置信区间52 - 83%）的特异性区分未来MTX治疗的无反应者与反应者。对于血清阳性患者（n = 44），这种趋势有所改善，无反应的敏感性为73%（95%置信区间45 - 92%），特异性为79%（95%置信区间60 - 92%）。
我们表明，IgG1的FA2/[FA2G1 + FA2G2]是一种生物标志物候选物，与无反应患者显著相关，对预测MTX临床反应具有潜在价值。
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