Randomized Controlled Trial

. 2025 Jul 1;185(7):808-816.

doi: 10.1001/jamainternmed.2025.1359.

Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis: A Randomized Clinical Trial

Zhaohua Zhu^{1

2}, Qinghong Yu³, Xiaomei Leng⁴, Jianhua Xu⁵, Limin Ren⁶, Kun Wang⁷, Cibo Huang⁸, Yunfeng Pan⁹, Yi Zhao¹⁰, Tianwang Li¹¹, Yifang Mei¹², Meihua Guan¹³, Xiaoxia Li¹⁰, Zhiyi Zhang¹⁴, Jing Wu³, Yingjuan Chen⁸, Yuan Qu³, Xiaotong Zhu³, Qiuju Liao¹⁰, Zhe Wang⁷, Zetao Liao⁹, Yang Xi¹², Weiming Deng¹¹, Kang Wang⁵, Tingting Zhu⁵, Yuping Zhang³, Lixia Gao¹³, Xiaoni Zhou¹, Weiyu Han^{1

15}, Guangfeng Ruan^{1

16}, Yan Zhang¹, Peihua Cao¹, Peichun Gao¹, Haowei Chen¹, Qin Dang¹, Flavia M Cicuttini¹⁷, David J Hunter^{1

2}, Zhanguo Li⁶, Xiaofeng Zeng⁴, Changhai Ding^{1

16

18}

Affiliations

¹ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
² Sydney Musculoskeletal Health and Royal North Shore Hospital, Kolling Institute, University of Sydney, Sydney, Australia.
³ Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Rheumatology and Clinical Immunology, Peking Union Medical Collage Hospital, Chinese Academy of Medical Science; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
⁵ Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁶ Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
⁷ Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁸ Department of Rheumatology, Beijing Hospital Affiliated to the National Health Commission, Beijing, China.
⁹ Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
¹⁰ Department of Rheumatology & Allergy, Xuanwu Hospital of Capital Medical University, Beijing, China.
¹¹ Department of Rheumatology, Guangdong Second People's Hospital, Guangzhou, China.
¹² Department of Rheumatology, Shenzhen Third People's Hospital, Shenzhen, China.
¹³ Department of Rheumatology, Central People's Hospital of Zhanjiang, Zhanjiang, China.
¹⁴ Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
¹⁵ Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
¹⁶ Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
¹⁷ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
¹⁸ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

PMID: 40455462
PMCID: PMC12131170 (available on 2026-06-02)
DOI: 10.1001/jamainternmed.2025.1359

Randomized Controlled Trial

Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis: A Randomized Clinical Trial

Zhaohua Zhu et al. JAMA Intern Med. 2025.

. 2025 Jul 1;185(7):808-816.

doi: 10.1001/jamainternmed.2025.1359.

Authors

Affiliations

¹ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
² Sydney Musculoskeletal Health and Royal North Shore Hospital, Kolling Institute, University of Sydney, Sydney, Australia.
³ Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Rheumatology and Clinical Immunology, Peking Union Medical Collage Hospital, Chinese Academy of Medical Science; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
⁵ Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁶ Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
⁷ Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
⁸ Department of Rheumatology, Beijing Hospital Affiliated to the National Health Commission, Beijing, China.
⁹ Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
¹⁰ Department of Rheumatology & Allergy, Xuanwu Hospital of Capital Medical University, Beijing, China.
¹¹ Department of Rheumatology, Guangdong Second People's Hospital, Guangzhou, China.
¹² Department of Rheumatology, Shenzhen Third People's Hospital, Shenzhen, China.
¹³ Department of Rheumatology, Central People's Hospital of Zhanjiang, Zhanjiang, China.
¹⁴ Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
¹⁵ Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
¹⁶ Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
¹⁷ Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.
¹⁸ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

PMID: 40455462
PMCID: PMC12131170 (available on 2026-06-02)
DOI: 10.1001/jamainternmed.2025.1359

Abstract

Importance: A recent study reported that methotrexate may reduce joint pain in patients with inflammatory hand osteoarthritis (OA). However, it remains unknown whether methotrexate has similar effects on inflammatory knee OA.

Objective: To examine whether methotrexate has symptom-relieving and disease-modifying effects for participants with knee OA and effusion-synovitis.

Design, setting, and participants: This multicenter, placebo-controlled randomized clinical trial was conducted at 11 sites in China between July 18, 2019, and January 15, 2023. Community-dwelling patients with inflammatory knee OA with effusion-synovitis on magnetic resonance imaging were included.

Interventions: Participants were randomly assigned (1:1) to receive methotrexate, up to 15 mg weekly, or placebo using block randomization, stratified by study site.

Main outcomes and measures: The primary outcomes were knee visual analog scale (VAS) pain change and effusion-synovitis maximal area change, over 52 weeks in the intention-to-treat population.

Results: Of 278 participants screened, 215 participants (mean [SD] age, 60.4 [7.4] years; 191 [89%] female) were randomized (108 to the methotrexate group; 107 to the placebo group), and 175 (81%) completed the trial. Changes in VAS pain and effusion-synovitis maximal area were not significantly different between the methotrexate and placebo group over 52 weeks (between-group difference, 0.3 mm [95% CI, -6.7 to 7.3 mm] for VAS pain; 0.1 cm2 [95% CI, -0.8 to 1.0 cm2] for effusion-synovitis maximal area). No significant between-group differences were found for any of the prespecified secondary outcomes. At least 1 adverse event occurred in approximately 32 participants (29.6%) in the methotrexate group and 26 participants (24.3%) in the placebo group.

Conclusions and relevance: The results of this randomized clinical trial show that, compared to placebo, low-dose methotrexate did not reduce pain or effusion-synovitis over 52 weeks in patients with knee OA and effusion-synovitis.

Trial registration: ClinicalTrials.gov Identifier: NCT03815448.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hunter reported providing consulting advice on scientific advisory boards for Pfizer, Lilly, Haleon, TLCBio, Novartis, Tissuegene, Biobone, Sanofi, and Enlivex outside the submitted work. No other disclosures were reported.

Comment on

The Future of Pharmaceuticals for Knee Osteoarthritis Needs to Move Past Methotrexate.
Lane NE. Lane NE. JAMA Intern Med. 2025 Jul 1;185(7):816-817. doi: 10.1001/jamainternmed.2025.1377. JAMA Intern Med. 2025. PMID: 40455439 No abstract available.

References

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Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis: A Randomized Clinical Trial

Affiliations

Low-Dose Methotrexate for the Treatment of Inflammatory Knee Osteoarthritis: A Randomized Clinical Trial

Authors

Affiliations

Abstract

Conflict of interest statement

Comment on

References

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Medical