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Analysis of biomarker serum levels in IVIG and infliximab refractory Kawasaki disease patients

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Abstract

Infliximab (IFX) is effective for treatment of refractory Kawasaki disease (KD). However, the precise mechanisms and biomarkers for IFX efficacy are unknown. We tried to evaluate the effect and response to IFX therapy by measuring serum cytokine levels. Twenty-nine children with KD who had been resistant to two courses of high-dose intravenous immunoglobulin were enrolled and treated with IFX. Plasma samples were analyzed for cytokines before and after IFX administration. Serum levels of interleukin-6, granulocyte colony-stimulating factor (G-CSF), interferon-gamma-induced monokine, interferon-gamma inducible protein 10 (IP-10), monocyte chemotactic protein 1, and soluble tumor necrosis factor-alpha receptor (sTNFR) 1 and 2 were significantly elevated before IFX treatment, but promptly decreased after the administration. The pre-treatment G-CSF and sTNFR1 levels in non-responders to IFX were significantly higher than in responders, who were defined as patients who defervesce (< 37.5 °C). After IFX administration, elevated cytokines declined to normal ranges in responders, but in non-responsive group, G-CSF and sTNFR1 remained elevated without failing to normal levels. IFX treatment significantly reduced the levels of serum cytokines, chemokines, and sTNFRs in refractory KD. G-CSF and sTNFR1 may be indicators predictive of poor response to IFX.

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Acknowledgements

We thank Drs. Fumio Morohashi, Kuniaki Naganuma, Kesashi Aonuma, Akihiko Yabuhara, Takahisa Tsuno, Tetsuo Kubo, Yasushi Iwasaki, Ei Shimazaki, Takashi Shimizu, and Kenichi Koike for their invaluable contributions to the collection of patient samples.

Source of funding

This work was supported by a Health Labour Sciences Research Grant entitled Translational research toward the clarification of autoinflammatory mechanisms by familial Mediterranean fever (FMF) inflammasomes based on the Mediterranean fever (MEFV) gene analysis (15ek0109033h0002).

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Correspondence to Kazunaga Agematsu.

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This investigation on IFX therapy for refractory KD and its analysis of cytokine profiles for KD were approved by the institutional review board of Shinshu University (No. 993 and 2781).

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Informed consent was obtained from all individual participants included in the study.

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Hachiya, A., Kobayashi, N., Matsuzaki, S. et al. Analysis of biomarker serum levels in IVIG and infliximab refractory Kawasaki disease patients. Clin Rheumatol 37, 1937–1943 (2018). https://doi.org/10.1007/s10067-017-3952-7

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