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

Jacqueline E Paramarta, Maureen C Turina, Troy Noordenbos, Tanja F Heijda, Iris C Blijdorp, Nataliya Yeremenko, Dominique Baeten, Jacqueline E Paramarta, Maureen C Turina, Troy Noordenbos, Tanja F Heijda, Iris C Blijdorp, Nataliya Yeremenko, Dominique Baeten

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.

Keywords: Mast cells; Nilotinib; Randomized controlled trial; Spondyloarthritis; Tyrosine kinase inhibitor.

Figures

Fig. 1
Fig. 1
Synovial tissue mRNA expression in peripheral spondyloarthritis. Effect of nilotinib and placebo treatment on in vivo synovial tissue mRNA expression in peripheral spondyloarthritis as assessed by quantitative polymerase chain reaction. The panel represents the transcription of c-Kit, interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF), and IL-23 before and after treatment with nilotinib (a–e) or placebo (f–j). The lines connect the data points for each patient between weeks (week) 0 and 12
Fig. 2
Fig. 2
Serum biomarkers in peripheral spondyloarthritis. Effect of nilotinib and placebo on serum biomarkers of patients with peripheral spondyloarthritis. The panel represents the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), calprotectin and matrix metalloproteinase-3 (MMP-3) levels before (week 0) and after treatment (week 12) with nilotinib (a–d) or placebo (e–h). The lines connect the data points for each patient. *P value <0.05
Fig. 3
Fig. 3
Clinical disease activity in peripheral spondyloarthritis. Changes in clinical disease activity parameters during treatment with nilotinib or placebo from week 0 until week 12, and during the open label extension phase with nilotinib from week 12 until week 24 in patients with peripheral spondyloarthritis. The panel represents the median (interquartile range) in patient’s global assessment of disease activity (a), physician’s global assessment of disease activity (b), swollen joint count (c), tender joint count (d), ankylosing spondylitis disease activity score (ASDAS) (e), and the percentage of patients achieving ASDAS clinically important improvement (f). *P value <0.05 compared to baseline
Fig. 4
Fig. 4
Serum biomarkers in axial spondyloarthritis. Effect of nilotinib and placebo on serum biomarkers of patients with axial spondyloarthritis. The panel represents the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), calprotectin and matrix metalloproteinase-3 (MMP-3) levels before (week 0) and after treatment (week 12) with nilotinib (a–d) or placebo (e–h). The lines connect the data points for each patient. *P value <0.05
Fig. 5
Fig. 5
Clinical disease activity in axial spondyloarthritis. Changes in clinical disease activity parameters during treatment with nilotinib or placebo from week 0 until week 12, and during the open label extension phase with nilotinib from week 12 until week 24 in patients with axial spondyloarthritis. The panel represents the median (interquartile range) in patient’s global assessment of disease activity (a), physician’s global assessment of disease activity (b), bath ankylosing spondylitis disease activity index (BASDAI) (c), ankylosing spondylitis disease activity score (ASDAS) (d), and the percentage of patients achieving a BASDAI50 response (e), and ASDAS clinically important improvement (f). *P value <0.05 compared to baseline

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