Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease
Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease
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DOI：
10.1182/blood-2008-05-155846
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发表时间：
2008-11-15
期刊：
影响因子：
20.3
通讯作者：
Kakehi, Takahiro
中科院分区：
文献类型：
--
作者：
Nishimoto, Norihiro;Terao, Kimio;Kakehi, Takahiro
白细胞介素-6（IL-6）在类风湿性关节炎（RA）、Castleman病等免疫炎症性疾病中起重要的病理作用。通过抑制IL-6受体（IL-6 R），托珠单抗（一种人源化抗IL-6 R抗体）可改善这些疾病的症状，并使包括C反应蛋白（CRP）在内的急性期蛋白正常化。我们发现托珠单抗治疗增加了血清IL-6和可溶性IL-6 R（sIL-6 R）水平。为了研究这些增加的病理意义，我们分析了RA和Castleman病患者托珠单抗给药后血清IL-6和sIL-6 R的动力学以及托珠单抗饱和的sIL-6 R的比例，然后将结果与CRP值进行比较。RA和Castleman病患者托珠单抗给药后血清IL-6和sIL-6 R均显著升高。只要可检测到游离托珠单抗，托珠单抗使sIL-6 R饱和，IL-6信号传导被完全抑制。我们得出结论，sIL-6 R增加可能是因为托珠单抗/sIL-6 R免疫复合物的形成延长了其消除半衰期，而游离血清IL-6增加可能是因为IL-6 R介导的IL-6消耗受到托珠单抗游离IL-6 R不可用的抑制。我们还得出结论，托珠单抗治疗期间游离IL-6水平的增加密切反映了实际的内源性IL-6产生和真实的疾病活动。（血。2008; 112：3959-3964）
Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity. (Blood. 2008; 112: 3959-3964)