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Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients

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Abstract

Introduction

Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). Frailty is the intermediate condition between being healthy and disabled, and can lead to negative health outcomes. Adverse events (AEs) due to RA drugs are expected to be higher in frail patients. The present study aimed to investigate the relationship between frailty and MTX discontinuation due to AEs in RA patients.

Methods

Of 538 RA patients who visited us between June and August 2020 as part of the retrospective T-FLAG study, 323 used MTX. After 2 years of follow-up, we investigated AEs leading to MTX discontinuation. Frailty was defined as a Kihon Checklist (KCL) score ≥ 8. Cox proportional hazards regression analysis was performed to identify factors associated with MTX discontinuation due to AEs.

Results

Of the 323 RA patients (251 women, 77.7%) who used MTX, 24 (7.4%) discontinued MTX due to AEs during the 2-year follow-up period. Mean ages in the MTX continuation/discontinuation groups were 64.5 ± 13.9/68.5 ± 11.7 years (p = 0.169), Clinical Disease Activity Index was 5.6 ± 7.3/6.2 ± 6.0 (p = 0.695); KCL was 5.9 ± 4.1/9.0 ± 4.9 points (p < 0.001); and the proportion of frailty was 31.8%/58.3% (p = 0.012). MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02–5.37) even after adjusting for age and diabetes mellitus. AEs included liver dysfunction (25.0%), pneumonia (20.8%), and renal dysfunction (12.5%).

Conclusions

Because frailty is a significant factor contributing to MTX discontinuation due to AEs, the latter should be carefully monitored in frail RA patients who use MTX.

Key Points

• Of the 323 rheumatoid arthritis (RA) patients (251 women, 77.7%) who used methotrexate (MTX), 24 (7.4%) discontinued MTX due to adverse events (AEs) during the 2-year follow-up period.

• MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02–5.37) even after adjusting for age and diabetes mellitus, and neither the MTX dose, folic acid supplementation, nor GC co-therapy were factors in MTX discontinuation.

• Frailty is a predominant factor in MTX discontinuation among established, long-term pretreated RA patients, and the occurrence of AEs due to MTX should be carefully monitored when frail RA patients use MTX.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Ms. Sachiko Kato, Ms. Emi Yokota, Ms. Ritsuko Otake, and Ms. Takako Sashikata for their assistance with information collection.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Japanese Red Cross Nagoya Daiichi Hospital, 3-35 Michishita, Nakamura, Nagoya, Aichi, 453-8511, Japan

    Yasumori Sobue, Hisato Ishikawa & Hidenori Inoue

  2. Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, Aichi, 466-8550, Japan

    Mochihito Suzuki, Yoshifumi Ohashi, Shuji Asai, Kenya Terabe, Kenji Kishimoto, Daisuke Kihira, Masataka Maeda, Ryo Sato & Shiro Imagama

  3. Department of Orthopedic Surgery, Japan Community Healthcare Organization Kani Tono Hospital, 1221-5 Dota, Kani, Gifu, 509-0206, Japan

    Mochihito Suzuki & Hiroshi Koshima

  4. Department of Orthopedic Surgery, Yokkaichi Municipal Hospital, 2-2-37 Shibata, Yokkaichi, Mie, 510-8567, Japan

    Yoshifumi Ohashi & Nobuyuki Okui

  5. Department of Orthopedic Surgery, Kariya Toyota General Hospital, 5-15 Sumiyoshi, Kariya, Aichi, 448-0852, Japan

    Koji Funahashi

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  1. Yasumori Sobue
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Contributions

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Sobue had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Yasumori Sobue: Study design, data collection, data analysis, and drafting the manuscript. Mochihito Suzuki, Yoshifumi Ohashi: drafting the manuscript, data collection, and data analysis. Hiroshi Koshima, Nobuyuki Okui, Hisato Ishikawa, Hidenori Inoue: drafting the manuscript and data collection. Koji Funahashi, Shuji Asai, Kenya Terabe, Shiro Imagama: drafting the manuscript and data analysis. Kenji Kishimoto, Daisuke Kihira, Masataka Maeda, Ryo Sato: drafting the manuscript.

Corresponding author

Correspondence to Yasumori Sobue.

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Ethics approval

This retrospective study was approved by the Ethics Committees of Nagoya University School of Medicine (2017–0271), Japanese Red Cross Nagoya Daiichi Hospital (2020–451), Japan Community Health Care Organization Kani Tono Hospital (20110901), and Yokkaichi Municipal Hospital (2017–29). We disclosed information pertaining to the study at the cooperating facilities according to the procedure stipulated by the respective Ethics Committees. Informed consent was obtained from all subjects. The study was conducted in accordance with the World Medical Association of Helsinki ethical principles for medical research involving human subjects.

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Sobue, Y., Suzuki, M., Ohashi, Y. et al. Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients. Clin Rheumatol 42, 2069–2077 (2023). https://doi.org/10.1007/s10067-023-06639-z

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