Paramarta Jacqueline E, Turina Maureen C, Noordenbos Troy, Heijda Tanja F, Blijdorp Iris C, Yeremenko Nataliya, Baeten Dominique
Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Laboratory of Experimental Immunology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
J Transl Med. 2016 Oct 27;14(1):308. doi: 10.1186/s12967-016-1050-2.
To evaluate the immunomodulating and clinical effects of nilotinib, a tyrosine kinase inhibitor, in a proof-of-concept study in spondyloarthritis (SpA) assessing the mast cell as potential novel therapeutic target in this disease.
Twenty eight patients with active peripheral (pSpA) and/or axial SpA (axSpA) were included in a randomized, double-blind, placebo-controlled clinical trial (Trial registration: Trialregister.nl NTR2834). Patients were treated 1:1 with nilotinib or placebo for 12 weeks, followed by an open label extension for another 12 weeks. Paired synovial tissue biopsies, serum sampling and assessment of clinical symptoms were performed serially.
In pSpA (n = 13) synovial inflammation appeared to diminish after 12 weeks of nilotinib treatment as evidenced by histopathology (decrease in number of infiltrating CD68+ and CD163+ macrophages and mast cells). Compared to placebo mRNA expression of c-Kit as mast cell marker (p = 0.037) and of pro-inflammatory cytokines such as IL-6 (p = 0.024) were reduced. The reduction of synovial inflammation was paralleled by a decrease in serum biomarkers of inflammation such as C-reactive protein (p = 0.024) and calprotectin (p = 0.055). Also clinical parameters such as patient's global assessment of disease activity (p = 0.031) and ankylosing spondylitis disease activity score (p = 0.031) showed improvement upon 12 weeks of nilotinib but not placebo treatment. This improvement was further augmented at week 24. In contrast to pSpA, neither serum biomarkers of inflammation nor clinical parameters improved upon nilotinib treatment in axSpA. During the trial one serious adverse event occurred, which was considered unrelated to the study drug.
This small proof-of-concept study suggests that nilotinib treatment modulates inflammation and clinical symptoms in pSpA. A similar effect was not seen in axSpA.
trialregister.nl registration code NTR2834 registered 31 March 2011.
在一项关于脊柱关节炎（SpA）的概念验证研究中，评估酪氨酸激酶抑制剂尼洛替尼的免疫调节作用和临床效果，该研究将肥大细胞视为这种疾病潜在的新型治疗靶点。
28例活动性外周型（pSpA）和/或中轴型SpA（axSpA）患者被纳入一项随机、双盲、安慰剂对照临床试验（试验注册号：Trialregister.nl NTR2834）。患者按1:1比例接受尼洛替尼或安慰剂治疗12周，随后进行为期12周的开放标签扩展试验。连续进行配对滑膜组织活检、血清采样及临床症状评估。
在pSpA（n = 13）中，尼洛替尼治疗12周后滑膜炎症似乎减轻，组织病理学证据显示（浸润的CD68 +和CD163 +巨噬细胞及肥大细胞数量减少）。与安慰剂相比，作为肥大细胞标志物的c-Kit（p = 0.037）以及促炎细胞因子如IL-6（p = 0.024）的mRNA表达降低。滑膜炎症的减轻与炎症血清生物标志物如C反应蛋白（p = 0.024）和钙卫蛋白（p = 0.055）的降低相平行。尼洛替尼治疗12周时，患者对疾病活动的整体评估（p = 0.031）和强直性脊柱炎疾病活动评分（p = 0.031）等临床参数也显示改善，而安慰剂治疗无此效果。这种改善在第24周时进一步增强。与pSpA相反，axSpA患者接受尼洛替尼治疗后，炎症血清生物标志物和临床参数均未改善。试验期间发生了1例严重不良事件，认为与研究药物无关。
这项小型概念验证研究表明，尼洛替尼治疗可调节pSpA的炎症和临床症状。axSpA未观察到类似效果。
trialregister.nl注册号NTR2834，于2011年3月31日注册
