Insights from pharmacovigilance databases, clinical cohorts and preclinical models into VEGF(R) inhibitor-induced arthritis in cancer

Lan Xu; Anqi Lin; Zhengrui Li; Junyi Shen; Hao Chi; Hank Z H Wong; Jian Zhang; Qi Wang; Jianying Xu; Pengpeng Zhang; Peng Luo

doi:10.1038/s43856-025-01169-y

Insights from pharmacovigilance databases, clinical cohorts and preclinical models into VEGF(R) inhibitor-induced arthritis in cancer

Commun Med (Lond). 2025 Nov 18;5(1):478. doi: 10.1038/s43856-025-01169-y.

Authors

Lan Xu^#¹, Anqi Lin^#¹, Zhengrui Li^#², Junyi Shen^#³, Hao Chi^#⁴, Hank Z H Wong^#⁵, Jian Zhang³, Qi Wang⁶, Jianying Xu⁷, Pengpeng Zhang⁸, Peng Luo⁹

Affiliations

¹ Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University); Department of Oncology, Zhujiang Hospital, Southern Medical University, Lianyungang, China.
² Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.
³ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
⁵ Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
⁶ Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. drwang71111@163.com.
⁷ Department of Medicine II, LMU University Hospital, Munich, Germany. jianying.xu@med.uni-muenchen.de.
⁸ Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. zpp19940120@tmu.edu.cn.
⁹ Donghai County People's Hospital (Affiliated Kangda College of Nanjing Medical University); Department of Oncology, Zhujiang Hospital, Southern Medical University, Lianyungang, China. luopeng@smu.edu.cn.

^# Contributed equally.

Abstract

Background: VEGF and VEGFR inhibitors are key in targeted therapy for various malignancies, but arthritis-related side effects are poorly understood. This study investigates the incidence, risk factors, and molecular mechanisms of VEGF(R) inhibitor-induced arthritis.

Methods: Statistical analyses of VEGF(R) inhibitor-related arthritis adverse events were conducted using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's global individual case safety reports database (VigiBase), with risk assessment performed using reporting odds ratio (ROR) and proportional reporting ratio (PRR). The effects of VEGF(R)i treatment on arthritis-related biomarkers were validated through the analysis of clinical data from cancer patients receiving VEGF(R)i therapy. A VEGF(R)i-treated mouse model was established using only male mice to investigate transcriptomic changes in bone tissue using high-throughput sequencing technology, thereby exploring potential mechanisms of VEGF(R)i-related arthritis.

Results: FAERS and VigiBase data show a significant link between VEGF(R) inhibitors and arthritis, with a higher incidence in females and individuals under 65. Clinical data reveal elevated inflammatory markers post-treatment. Transcriptomic analysis shows the activation of some and suppression of other inflammation-related pathways in bone tissue after VEGF(R) inhibitor treatment.

Conclusions: This study provides a systematic analysis of VEGF(R) inhibitor-related arthritis, reveals its incidence patterns and potential molecular mechanisms, and offers insights into prevention and treatment strategies for this side effect in clinical practice.

Plain language summary

VEGF(R) inhibitors that are used to treat cancer may induce arthritis. This adverse effect remains inadequately characterized. We evaluated the incidence, risk factors, and underlying mechanisms of this condition. We looked at indicators of inflammation in people with cancer and mice being treated with VEGF(R) inhibitors. There was an increased risk of arthritis in people treated with VEGF(R) inhibitors, particularly among females and individuals under 65 years of age. Increased inflammatory responses were observed in people and mice. These findings provide information about why this adverse event occurs and could contribute to the development of improved strategies for the prevention and management of this treatment-related adverse event, ultimately improving oncology care.