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

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

doi:10.1186/s12967-016-1050-2

Abstract

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

Highlights

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
We recently proposed that mast cells might be more important in SpA than in rheumatoid arthritis (RA) based on the following: [13] Firstly, the infiltration with c-Kit + mast cells in SpA synovitis is markedly higher compared to RA
This was confirmed by qPCR analysis of mRNA expression, as c-Kit expression showed a significant decrease upon nilotinib treatment but augmented upon placebo treatment over 12 weeks (p = 0.037) (Fig. 1a)

Summary

Introduction

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. We recently proposed that mast cells might be more important in SpA than in rheumatoid arthritis (RA) based on the following: [13] Firstly, the infiltration with c-Kit + mast cells in SpA synovitis is markedly higher compared to RA. This infiltration is already observed in early disease and is not affected by effective anti-TNF treatment. Sulfasalazine, the only disease-modifying anti-rheumatic drug (DMARD) with proven efficacy in pSpA [17], has shown to inhibit degranulation and TNF secretion by mast cells [18, 19]

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