Background/Purpose:

Immunopathological studies on synovitis recently identified the mast cell as potential novel therapeutic target in spondyloarthritis (SpA).[1] Mast cells can be targeted by inhibiting the signalling of c-Kit, which is one of the targets of the tyrosine kinase inhibitor nilotinib. The aim of this study was to evaluate the immunomodulating and clinical effects of nilotinib in the treatment of SpA.

Methods:

28 patients with active peripheral and/or axial SpA were included in a randomized, double-blind, placebo-controlled clinical trial. 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 peripheral SpA (n=13) synovial inflammation was markedly reduced 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 the 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 improvement of synovial inflammation was paralleled by a decrease in serum biomarkers of inflammation such as C-reactive protein (CRP) from 9.2 (IQR 1.7-33.1) to 5.2 (IQR 1.7-25.1) mg/L (p=0.024) and calprotectin from 359.9 (IQR 183.3-484.9) to 287.9 (IQR 116.7-457.1) ng/mL (p=0.055). Also clinical parameters such as patient’s global assessment of disease activity (week 0: 52 (IQR 43-65) vs week 12: 21 (IQR 0-51) mm; p=0.031) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (week 0: 2.2 (IQR 1.2-3.0) vs week 12: 1.1 (IQR 0.7-2.4); p=0.031) showed improvement upon 12 weeks of nilotinib but not placebo treatment, and this improvement was further augmented at week 24. In sharp contrast to peripheral SpA, neither serum biomarkers of inflammation nor clinical parameters improved upon nilotinib treatment in axial SpA. During the trial one serious adverse event occurred, which was considered unrelated to the study drug. There were no unexpected safety signals in comparison with published large scale data on nilotinib in chronic myeloid leukemia (CML).

Conclusion:

This proof-of-concept study supports the concept that mast cells can contribute to synovial inflammation in SpA and that tyrosine kinase inhibition targeting these cells has a biological and clinical immunomodulatory effect in peripheral but not axial SpA. These results support further clinical evaluation of nilotinib in larger clinical trials in pure peripheral SpA, as well as evaluation of other drugs targeting mast cells in SpA.

References

¹Noordenbos T, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99-109.

Acknowledgements

We thank Novartis for the supply of the study medication for this investigator initiated and independent study.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-synovial-mast-cells-in-spondyloarthritis-a-proof-of-concept-study-with-the-tyrosine-kinase-inhibitor-nilotinib/