A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis
Abstract Background 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. Methods Twenty eight patients with active periphe...
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doaj-722a83161dc94d20834e95355bb29e412020-11-25T00:46:41ZengBMCJournal of Translational Medicine1479-58762016-10-0114111110.1186/s12967-016-1050-2A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritisJacqueline E. Paramarta0Maureen C. Turina1Troy Noordenbos2Tanja F. Heijda3Iris C. Blijdorp4Nataliya Yeremenko5Dominique Baeten6Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamDepartment of Clinical Immunology and Rheumatology, Academic Medical Center/University of AmsterdamAbstract Background 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. Methods 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. Results 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. Conclusions 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. Trial registration: trialregister.nl registration code NTR2834 registered 31 March 2011http://link.springer.com/article/10.1186/s12967-016-1050-2SpondyloarthritisNilotinibTyrosine kinase inhibitorRandomized controlled trialMast cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jacqueline E. Paramarta Maureen C. Turina Troy Noordenbos Tanja F. Heijda Iris C. Blijdorp Nataliya Yeremenko Dominique Baeten |
spellingShingle |
Jacqueline E. Paramarta Maureen C. Turina Troy Noordenbos Tanja F. Heijda Iris C. Blijdorp Nataliya Yeremenko Dominique Baeten A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis Journal of Translational Medicine Spondyloarthritis Nilotinib Tyrosine kinase inhibitor Randomized controlled trial Mast cells |
author_facet |
Jacqueline E. Paramarta Maureen C. Turina Troy Noordenbos Tanja F. Heijda Iris C. Blijdorp Nataliya Yeremenko Dominique Baeten |
author_sort |
Jacqueline E. Paramarta |
title |
A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
title_short |
A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
title_full |
A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
title_fullStr |
A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
title_full_unstemmed |
A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
title_sort |
proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis |
publisher |
BMC |
series |
Journal of Translational Medicine |
issn |
1479-5876 |
publishDate |
2016-10-01 |
description |
Abstract Background 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. Methods 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. Results 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. Conclusions 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. Trial registration: trialregister.nl registration code NTR2834 registered 31 March 2011 |
topic |
Spondyloarthritis Nilotinib Tyrosine kinase inhibitor Randomized controlled trial Mast cells |
url |
http://link.springer.com/article/10.1186/s12967-016-1050-2 |
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