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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Main Authors: Jacqueline E. Paramarta, Maureen C. Turina, Troy Noordenbos, Tanja F. Heijda, Iris C. Blijdorp, Nataliya Yeremenko, Dominique Baeten
Format: Article
Language:English
Published: BMC 2016-10-01
Series:Journal of Translational Medicine
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12967-016-1050-2
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spelling 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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