Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M, Hoelzl M, Khalil M, Killestein J, Lindberg R, Malucchi S, Mehling M, Montalban X, Polman C H, Rudzki D, Schautzer F, Sellebjerg F, Sørensen P S, Deisenhammer F
Department of Neurology, Innsbruck Medical University, Austria.
Mult Scler. 2014 Apr;20(5):577-87. doi: 10.1177/1352458513503597. Epub 2013 Sep 5.
Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy.
To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution.
We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.
We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples.
BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.
中和抗体（NAb）会影响干扰素-β（IFN-β）治疗多发性硬化症（MS）患者的疗效。高达44%的接受治疗的患者会产生NAb，通常在治疗6至18个月之间。
研究早期结合抗体（BAb）滴度或不同的IFN-β生物标志物是否能预测NAb的产生。
在这项前瞻性欧洲多中心研究中，我们纳入了接受初治IFN-β治疗的MS或临床孤立综合征（CIS）患者。在基线、首次给予IFN-β之前和之后以及治疗3、12和24个月后采集血样；用于检测NAb、BAb、MxA的基因表达以及MMP-9、TIMP-1、sTRAIL、CXCL-10和CCL-2的蛋白浓度。
我们发现，164例患者中有22例（13.4%）在接受IFN-β治疗的中位时间23.8个月期间产生了NAb。在这些患者中，78.9%在3个月后BAb呈阳性。BAb滴度≥1:2400预测NAb产生的敏感性为74.7%，特异性为98.5%。横断面分析显示，BAb/NAb阳性样本中的MxA水平显著降低；同样，与BAb/NAb阴性样本相比，BAb/NAb阳性和BAb阳性/NAb阴性样本中的CXCL-10和sTRAIL浓度也分别降低。
BAb滴度可可靠地预测NAb。CXCL-10是一种有前景的敏感生物标志物，可用于评估IFN-β反应及其被抗IFN-β抗体消除的情况。
