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The effectiveness of tocilizumab in treating refractory adult-onset Still’s disease with dichotomous phenotypes: IL-18 is a potential predictor of therapeutic response

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Abstract

Objective

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder with clinical heterogeneity. Although tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, is an effective treatment for AOSD, the evidence regarding its efficacy on systemic or articular subtypes is conflicting. Furthermore, the predictors of therapeutic response are still elusive and worthy of exploration.

Methods

This two-center retrospective study analyzed the effectiveness and safety profile of TCZ treatment in 28 patients with refractory AOSD. The 28-joint disease activity score (DAS28) and systemic activity score were assessed before and during TCZ treatment period at weeks 12, 24, 36, and 48. Plasma levels of proinflammatory cytokines at baseline were determined using ELISA method.

Results

Among the systemic subtype patients, 10 (58.8%), 13 (76.5%), 14 (82.4%), and 15 (88.2%) patients achieved complete remission at week 12, 24, 36, and 48, respectively, in comparison to 2 (22.2%), 5 (55.6%), 6 (66.7%), and 7 (77.8%) who achieved disease remission (DAS28 < 2.6) at weeks 12, 24, 36, and 48, respectively, among articular subtype patients. The systemic activity scores and inflammatory parameters were significantly decreased after 12-week TCZ therapy, and TCZ could significantly reduce corticosteroid dose in AOSD patients. Multivariate analysis reveals that baseline IL-18 level is a significant predictor of poor therapeutic response at week 24 (odds ratio 7.86, p < 0.05).

Conclusion

AOSD patients refractory to high-dose corticosteroids and methotrexate may respond well to TCZ treatment with a steroid-sparing effect and an acceptable safety. A high baseline IL-18 level may be a predictor of poor therapeutic response.

Key Points

• Tocilizumab may be effective and well-tolerated in refractory AOSD patients regardless of disease subtypes.

• High plasma levels of IL-18 may predict poor response to tocilizumab in AOSD patients.

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Acknowledgements

The authors thank Shiow-Jiuan Wey, MD, of the Chung Shan Medical University Hospital, Taiwan, for manuscript editing. The authors also thank the Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan.

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Author notes

  1. Kuo-Tung Tang and Chia-Wei Hsieh contributed equally to this paper.

Authors and Affiliations

  1. Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan

    Kuo-Tung Tang, Chia-Wei Hsieh, Hsin-Hua Chen, Yi-Ming Chen, Shih-Hsin Chang & Der-Yuan Chen

  2. Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan

    Kuo-Tung Tang, Chia-Wei Hsieh & Yi-Ming Chen

  3. Faculty of Medicine, National Yang Ming University, Taipei, Taiwan

    Kuo-Tung Tang, Hsin-Hua Chen & Yi-Ming Chen

  4. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Hsin-Hua Chen & Yi-Ming Chen

  5. Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan

    Hsin-Hua Chen

  6. Rheumatology and Immunology Center, China Medical University Hospital, No. 2, Yude Road, Taichung, 40447, Taiwan

    Shih-Hsin Chang, Po-Hao Huang, Joung-Liang Lan & Der-Yuan Chen

  7. College of Medicine, China Medical University, Taichung, Taiwan

    Shih-Hsin Chang, Po-Hao Huang, Joung-Liang Lan & Der-Yuan Chen

  8. Translational Medicine Laboratory, Rheumatology and Immunology Center, Taichung, Taiwan

    Der-Yuan Chen

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Contributions

K-TT and C-WH contributed equally on this work, conceived the study, acquired the clinical data, performed the data analysis, and drafted and revised the manuscript. Both Y-MC, S-HC, and H-HC performed the clinical assessment as well as data acquisition and statistical analysis. P-HH and J-LL performed the clinical assessments on study subjects and conducted the analysis of data. D-YC conceived and designed the study, generated the original hypothesis, acquired the clinical data, performed the data analysis, and also revised the manuscript.

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Correspondence to Der-Yuan Chen.

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Tang, KT., Hsieh, CW., Chen, HH. et al. The effectiveness of tocilizumab in treating refractory adult-onset Still’s disease with dichotomous phenotypes: IL-18 is a potential predictor of therapeutic response. Clin Rheumatol 41, 557–566 (2022). https://doi.org/10.1007/s10067-021-05921-2

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