A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis

Journal of Translational Medicine

Research

Jacqueline E. Paramarta¹  Tanja F. Heijda¹  Maureen C. Turina¹  Iris C. Blijdorp²  Nataliya Yeremenko²  Troy Noordenbos²  Dominique Baeten² 

[1] Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;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;

关键词: Spondyloarthritis;    Nilotinib;    Tyrosine kinase inhibitor;    Randomized controlled trial;    Mast cells;   

DOI  :  10.1186/s12967-016-1050-2

 received in 2016-01-22, accepted in 2016-10-05,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTo 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.MethodsTwenty 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.ResultsIn 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.ConclusionsThis small proof-of-concept study suggests that nilotinib treatment modulates inflammation and clinical symptoms in pSpA. A similar effect was not seen in axSpA.Trial registration: trialregister.nl registration code NTR2834 registered 31 March 2011

【 授权许可】

CC BY   
© The Author(s) 2016