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Plasma IL-36α and IL-36γ as Potential Biomarkers in Interstitial Lung Disease Associated with Rheumatoid Arthritis: a Pilot Study in the Chinese Population

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Abstract

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40 pg/mL and that for distinguishing RA-ILD from IPF was 655.10 pg/mL. No significant difference in plasma IL-36β or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF.

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Funding

The work was supported by funds from the National Natural Science Foundation of China (Grant Nos. 82070062 and 81870057), the Natural Science Foundation of Hubei Province (Grant No. 2020CFA018), the Climbing Project for Medical Talent of Zhongnan Hospital, Wuhan University (Grant No. PDJH202205), and the Science, Technology and Innovation Seed Fund of Zhongnan Hospital of Wuhan University (Grant No: znpy2019052).

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  1. Weishuai Zheng, Xingxing Hu and Menglin Zou contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Weishuai Zheng, Xingxing Hu, Menglin Zou, Weiwei Song, Rui Wang, Ying Liu, Qinhui Hou, Yuan Liu & Zhenshun Cheng

  2. Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Nie Hu & Xiaoqi Chen

  3. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Zhenshun Cheng

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Contributions

Yuan Liu, Xiaoqi Chen, and Zhenshun Cheng contributed to the study conception and design. Data and sample collection was performed by Weishuai Zheng, Xingxing Hu, Menglin Zou, Nie Hu, Weiwei Song, Rui Wang, Ying Liu, and Qinhui Hou. The preparation of material, experiment operation, and data analysis were performed by Weishuai Zheng, Xingxing Hu, and Menglin Zou. The first draft of the manuscript was written by Weishuai Zheng, and all authors commented on previous versions of the manuscript. Weishuai Zheng, Xingxing Hu, and Menglin Zou contributed equally to this work and share first authorship. Yuan Liu, Xiaoqi Chen, and Zhenshun Cheng contributed equally to this work. The authors read and approved the final manuscript.

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Correspondence to Yuan Liu, Xiaoqi Chen or Zhenshun Cheng.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval for the study was granted by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University.

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Zheng, W., Hu, X., Zou, M. et al. Plasma IL-36α and IL-36γ as Potential Biomarkers in Interstitial Lung Disease Associated with Rheumatoid Arthritis: a Pilot Study in the Chinese Population. Inflammation 46, 285–296 (2023). https://doi.org/10.1007/s10753-022-01733-x

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