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

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Learn more: PMC Disclaimer | PMC Copyright Notice JAMA Intern Med . 2025 Jun 2;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, 17 , Qinghong Yu 2 , Xiaomei Leng 3 , Jianhua Xu 4 , Limin Ren 5 , Kun Wang 6 , Cibo Huang 7 , Yunfeng Pan 8 , Yi Zhao 9 , Tianwang Li 10 , Yifang Mei 11 , Meihua Guan 12 , Xiaoxia Li 9 , Zhiyi Zhang 13 , Jing Wu 2 , Yingjuan Chen 7 , Yuan Qu 2 , Xiaotong Zhu 2 , Qiuju Liao 9 , Zhe Wang 6 , Zetao Liao 8 , Yang Xi 11 , Weiming Deng 10 , Kang Wang 4 , Tingting Zhu 4 , Yuping Zhang 2 , Lixia Gao 12 , Xiaoni Zhou 1 , Weiyu Han 1, 14 , Guangfeng Ruan 1, 15 , Yan Zhang 1 , Peihua Cao 1 , Peichun Gao 1 , Haowei Chen 1 , Qin Dang 1 , Flavia M Cicuttini 16 , David J Hunter 1, 17 , Zhanguo Li 5 , Xiaofeng Zeng 3, ✉ , Changhai Ding 1, 15, 18, ✉ Author information Article notes Copyright and License information 1 Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China 2 Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China 3 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 4 Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China 5 Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China 6 Department of Joint and Trauma Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China 7 Department of Rheumatology, Beijing Hospital Affiliated to the National Health Commission, Beijing, China 8 Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China 9 Department of Rheumatology & Allergy, Xuanwu Hospital of Capital Medical University, Beijing, China 10 Department of Rheumatology, Guangdong Second People’s Hospital, Guangzhou, China 11 Department of Rheumatology, Shenzhen Third People’s Hospital, Shenzhen, China 12 Department of Rheumatology, Central People’s Hospital of Zhanjiang, Zhanjiang, China 13 Department of Rheumatology, The First Affiliated Hospital of Harbin Medical University, Harbin, China 14 Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China 15 Clinical Research Centre, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China 16 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia 17 Sydney Musculoskeletal Health and Royal North Shore Hospital, Kolling Institute, University of Sydney, Sydney, Australia 18 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia Accepted for Publication: February 21, 2025. Published Online: June 2, 2025. doi: 10.1001/jamainternmed.2025.1359 ✉ Corresponding Authors: Changhai Ding, PhD, MD, Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China ( changhai.ding@utas.edu.au ); Xiaofeng Zeng, MD, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China ( xiaofeng.zeng@cstar.org.cn ). Author Contributions: Dr Z. Zhu and Dr Ding had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Z. Zhu, Yu, and Leng contributed equally. Concept and design: Z. Zhu, Leng, Xu, Kun Wang, Huang, Pan, T. Li, Mei, X. Li, Y. Chen, Qu, Kang Wang, Han, Cicuttini, Zeng, Ding. Acquisition, analysis, or interpretation of data: Z. Zhu, Yu, Leng, Ren, Zhao, Guan, X. Li, Z. Zhang, Wu, Qu, X. Zhu, Q. Liao, Z. Wang, Z. Liao, Xi, Deng, T. Zhu, Yuping Zhang, L. Gao, Zhou, Ruan, Yan Zhang, Cao, P. Gao, H. Chen, Dang, Hunter, Z. Li, Ding. Drafting of the manuscript: Z. Zhu, Leng, Ren, Qu, Q. Liao, Xi, Deng, Zhou, Han, Cicuttini. Critical review of the manuscript for important intellectual content: Z. Zhu, Yu, Leng, Xu, Ren, Kun Wang, Huang, Pan, Zhao, T. Li, Mei, Guan, X. Li, Z. Zhang, Wu, Y. Chen, Qu, X. Zhu, Z. Wang, Z. Liao, Kang Wang, T. Zhu, Yuping Zhang, L. Gao, Han, Ruan, Yan Zhang, Cao, P. Gao, H. Chen, Dang, Cicuttini, Hunter, Z. Li, Zeng, Ding. Statistical analysis: Z. Zhu, Yu, Leng, Guan, Z. Zhang, Qu, X. Zhu, Xi, Deng, Yuping Zhang, L. Gao, Cao, P. Gao, H. Chen, Dang. Obtained funding: Z. Zhu, Leng, Qu, Deng, Han, Ding. Administrative, technical, or material support: Z. Zhu, Yu, Leng, Xu, Huang, Pan, Zhao, T. Li, Mei, X. Li, Z. Zhang, Y. Chen, Qu, X. Zhu, Q. Liao, Z. Wang, Z. Liao, Deng, Kang Wang, Yuping Zhang, Zhou, Han, Cicuttini, Hunter, Z. Li, Ding. Supervision: Yu, Xu, Kun Wang, Huang, Pan, X. Li, Wu, Qu, Deng, Kang Wang, Zeng, Ding. 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. Funding/Support: National Key Research & Development Program of China. This work was supported by the National Key Research & Development Program of China (2023YFE0209700), the National Natural Science Foundation of China (grant 82373653, 82372428), and the Clinical Research Startup Program of Southern Medical University, provided by High-level University Construction Funding of Guangdong Provincial Department of Education (grant LC2019ZD015). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Data Sharing Statement: See Supplement 3 . Additional Contributions: We express our gratitude to all the participants who made this study possible. We thank all participating institutions and their staff for their contribution to this study, particularly the research nurses and physician assistants. We also thank the following professionals for their compensated role in the coordination and execution of the study from Zhujiang Hospital: Huiqun Rong, MD, Qiqi Cheng, BSN, Bibo Liang, MD, Jiaxin Deng, MD, and Xiaorui Shi MSurg; The Third Affiliated Hospital of Sun Yat-sen University: Ying Xu, MD, Huimin Zhan, MD, and Ting Chen, MD; Peking University People’s Hospital: Jian Zhang, MD, and Di Jin, MD; Peking Union Medical College Hospital: Hanqi Wang, BSN, and Yan Zhang, PhD; Beijing Hospital Affiliated to the National Health Commission: Yuqing Ma, MD, and Xin Gao, MD; Xuanwu Hospital of the Capital Medical University: Lian Wei, BSN; Central People’s Hospital of Zhanjiang: Cailing Zhong, MD, Yan Chen, MD, Shanshan Chen, MD, Yemei Li, MD, and Guang Huang, MD; Shenzhen Third People’s Hospital: Shangqi Guan, MD; Guangdong Second People’s Hospital: Yukai Huang, MD; The First Affiliated Hospital of Anhui Medical University: Yangfan Chen, MD; Qingyuan People’s Hospital: Xiang Peng, MD. We thank SPH Sine Pharmaceutical Factory Co., Ltd (Shanghai, China), which provided methotrexate and placebo. ✉ Corresponding author. Received 2024 Dec 8; Accepted 2025 Feb 21; Issue date 2025 Jul. Copyright 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies. PMC Copyright notice PMCID: PMC12131170  PMID: 40455462 See commentary " The Future of Pharmaceuticals for Knee Osteoarthritis Needs to Move Past Methotrexate. " with doi: 10.1001/jamainternmed.2025.1377. Key Points Question Does low-dose methotrexate reduce pain and effusion-synovitis in patients with inflammatory knee osteoarthritis? Findings This multicenter, placebo-controlled randomized clinical trial of 215 patients with inflammatory knee osteoarthritis and effusion-synovitis demonstrated no statistically significant difference in knee pain or effusion-synovitis area changes between the methotrexate and placebo groups over 52 weeks. Meaning The findings do not support the use of methotrexate for symptom relief or disease modification in people with inflammatory knee osteoarthritis. 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 cm 2 [95% CI, −0.8 to 1.0 cm 2 ] 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 This randomized clinical trial investigates whether methotrexate has symptom-relieving and disease-modifying effects for participants with inflammatory knee osteoarthritis and effusion-synovitis. Introduction Osteoarthritis (OA) is a chronic joint disease and a leading cause of joint pain, loss of function, and disability among older adults. With more than 595 million people affected worldwide, OA is one of the most prevalent disorders in older adults, placing a considerable burden on patients and society. 1 , 2 The knee is the most common site for OA, making up more than 50% of the total OA population. 3 Despite the high prevalence and substantial disease burden, current treatments are limited as there are no disease-modifying therapies for knee OA. 4 Joint effusion shown on noncontrast T2-weighted or proton density–weighted magnetic resonance imaging (MRI) reflects a composite of true effusion and synovial thickening, known as effusion-synovitis. 5 Previous epidemiological studies reported that effusion-synovitis was highly prevalent in people with knee OA (more than 46%), and was significantly associated with increased knee pain. 6 Moreover, effusion-synovitis volume and maximal area were significantly associated with knee structural abnormalities such as cartilage defects, bone marrow lesions, and cartilage volume loss, 7 and predicted increased risk of joint replacement. 8 Therefore, effusion-synovitis is regarded as a sign of inflammatory phenotype and a potential treatment target for knee OA. Methotrexate is a slow-acting disease-modifying antirheumatic drug and the first-line treatment for synovitis in inflammatory arthritis such as rheumatoid arthritis. 9 An open-label study including 30 participants suggested that low-dose methotrexate, up to 20 mg, may have analgesic efficacy for knee OA at 24 weeks, warranting further investigation through a randomized clinical trial. 10 Results of the latest randomized clinical trial suggest that methotrexate treatment, up to 25 mg weekly for 6 months, could modestly reduce knee pain assessed by the numeric rating scale compared to placebo, yet had no effects on knee pain assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in 155 patients with symptomatic knee OA (PROMOTE trial). 11 A multisite randomized clinical trial (METHODS trial) 12 conducted by a member of our team compared methotrexate and placebo in participants with hand OA and MRI-detected synovitis scores of more than 1. After a 6-month follow-up, methotrexate, up to 20 mg once weekly, exhibited a moderate but potentially clinically meaningful effect on hand pain. In contrast, Ferrero et al 13 conducted a single-center trial of 64 participants with erosive hand OA and found that weekly doses of methotrexate, 10 mg, did not significantly reduce pain at 3 or 12 months. Taken together, these findings suggest an effect of methotrexate for inflammatory hand OA and a potential effect for knee OA. However, they also highlight the importance of phenotyping participants with knee OA to determine which specific populations, if any, will respond favorably to methotrexate. To date, no randomized clinical trial has investigated the efficacy of methotrexate in patients with inflammatory knee OA to our knowledge. Therefore, we performed the Methotrexate on Effusion-synovitis and Symptoms in Knee Osteoarthritis (MESKO) multicenter randomized clinical trial to compare the effect of low-dose methotrexate with placebo on knee pain and effusion-synovitis in participants with inflammatory knee OA over 52 weeks. Methods Study Design and Participants This investigator-initiated, multicenter, placebo-controlled randomized clinical trial was conducted from July 18, 2019, to January 15, 2023, in a community of 11 sites in China, and overseen by an independent data and safety monitoring board assembled by the trial steering committee (see trial protocol in Supplement 1 ; eMethods in Supplement 2 ). The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The MESKO study protocol and informed consent documentation were reviewed and approved by the institutional review board and the independent ethics committee of each investigational center before patient enrollment began. All participants provided written informed consent. The published study protocol 14 and the statistical analysis plan ( Supplement 1 ) were reported following the Standard Protocol Items: Recommendations for Interventional Trials ( SPIRIT ) reporting guideline, and the present trial adhered to the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline. Community-dwelling participants with knee OA and effusion-synovitis on MRI were recruited from several Chinese cities, including Guangzhou, Beijing, Hefei, Zhanjiang, Shenzhen, and Qingyuan, through advertisements and referrals from medical practitioners. Participant screening took place between July 18, 2019, and January 7, 2022. Detailed inclusion and exclusion criteria can be found in the eMethods in Supplement 2 . Physical examination for signs of inflammation (at least 2 of the following 4 clinical signs of inflammation: warmth over the joint area, joint margin tenderness, synovial effusion, and soft tissue swelling around the knee) was conducted before screening by rheumatologists or orthopedic surgeons. All participants were assessed by a rheumatologist or orthopedic surgeon to determine their eligibility. Randomization, Allocation Concealment, and Blinding We randomly assigned participants (1:1) to receive methotrexate or an identical inert placebo. Block randomization was conducted using computer-generated random numbers with a block size of 8, stratified by site. An independent statistician preserved and distributed each participant’s randomization number. The characteristics (eg, appearance, size, color, odor, taste), route, and administration of the assigned intervention were identical in both groups. Allocation concealment was ensured by the following measures: the use of a central automated allocation procedure with security in place; study medication and identical placebo tablet being dispensed by the hospital clinical trial pharmacy at each site; a unique randomization number linked each participant with identical study medication or placebo adminstered; researchers collected data masked to group allocation; and imaging being assessed by trained observers masked to group allocation and time sequence of imaging. Participants, investigators, physicians, pharmacists, monitors, outcome assessors, and statisticians were all blinded throughout the initial treatment, dose escalation, treatment withdrawal, adverse event management, data acquisition, and statistical analyses. Intervention, Concomitant Treatments, and Prohibited Medications After randomization, participants received methotrexate or an identical inert placebo, starting from methotrexate, 5 mg weekly for the first 2 weeks, and increasing to methotrexate, 10 mg weekly for the second 2 weeks, and increasing to methotrexate, 15 mg weekly for the remaining period, if tolerated. This dosage is the standard treatment dosage of methotrexate for Chinese patients with inflammatory arthritis, considering the balance between safety and efficacy. 15 , 16 Although the rheumatologists were blinded throughout the conduct of the trial, the dosage could be modified at the rheumatologist’s discretion due to intolerance or abnormal laboratory results. To reduce possible adverse effects, weekly doses of folic acid, 5 mg, were given to all participants 1 day after methotrexate or placebo administration. 17 Participants were not asked to stop their medications (eg, supplements, analgesics, herbal medicines), except for corticosteroids and antisynovitis medication. Trimethoprim, an antibiotic often used for respiratory and urinary infections, was not allowed because it could increase the toxic effects of methotrexate. Alcohol was avoided while participating in this trial. Outcome Measures The primary outcomes were changes in visual analog scale (VAS)–assessed knee pain (0-100 mm) and MRI-detected effusion-synovitis maximal area over 52 weeks, which informed the sample size calculations. Knee effusion-synovitis maximal area was measured as the presence of an intra-articular fluid-equivalent signal at screening and week 52 on sagittal T2-weighted or equivalent MRI sequences using a prespecified method. A maximal area in 1 slice was selected to represent the effusion-synovitis area of the knee. 18 The baseline and follow-up images were read in pairs without known-time order. To assess the reliability of the effusion-synovitis measurements, an experienced radiographer reevaluated 30 randomly selected MRI scans at an interval of more than 1 month, and an orthopedic surgeon evaluated these images. The intraclass correlation coefficients were 0.81 to 0.90 for intraobserver reproducibility and were 0.80 to 0.95 for interobserver reproducibility. A change in the effusion-synovitis maximal area was calculated by subtracting the baseline maximal area from the follow-up maximal area. Three MRI machine vendors (GE, Siemens, and Philips) were used across study centers. Quality control and MRI measurements were performed according to the detailed instructions in the study protocol and manual. The prespecified secondary outcomes were WOMAC total score and subscales that were assessed by VAS (0-100 mm) at each time point, infrapatellar fat pad (IPFP) signal intensity alteration (standard deviation and clustering factor) measured by T2-weighted MRI or equivalent sequences, 19 and responder criteria developed by the Outcome Measures in Rheumatology Arthritis Clinical Trials–Osteoarthritis Research Society International (OMERACT-OARSI) responders. 20 Knee effusion-synovitis volume was also assessed using T2-weighted MRI or equivalent sequences. The volumes of individual joint subregions (central portion, posterior femoral recess, suprapatellar pouch, and subpoliteal recess) were assessed by selecting each region of interest according to the intra-articular fluid-equivalent signal on a section-by-section basis. The final 3-dimensional volume rendering was generated using commercial in-house OsiriX Lite imaging software, 64-bit version 12.0.3 (Pixmeo SARL). 21 The readers were blinded to treatment allocation and participants’ information. There was a misprint in Table 1 of the published protocol that wrongly presented effusion-synovitis volume as the primary outcome. 14 The intrarater reliability, expressed as intraclass correlation coefficients, was 0.93 to 0.99 in different subregions. Other prespecified outcomes, such as the Patient Health Questionnaire–9 (PHQ-9), the Short Form–12 (SF-12), general health status, bone marrow lesion maximal area, and semiquantitative structural abnormalities, including effusion-synovitis score, IPFP signal intensity score, and cartilage defects, were assessed as described in the published trial protocol. 14 Concomitant medication uses, such as glucosamine and nonsteroidal anti-inflammatory drugs, were recorded at each visit. Adverse events were monitored throughout the trial. Participants were asked to report any adverse events to the research team at each visit and by telephone calls between the study visits after randomization. Results of blood tests (full blood count, kidney and liver function) were monitored at screening, weeks 4, 12, 24, 36, 52, and at withdrawal. Serious adverse events were assessed and reported to the ethics committees. Sample Size Sample size calculations were performed based on 2 primary outcomes and the Cohen formula, 22 assuming 2-sided α = .05, β = .20, and power = 80%. An observational study 7 reported that the mean (SD) suprapatellar pouch effusion-synovitis maximal area in older people with knee pain was 2.0 (1.5) cm 2 . To achieve the expected 35% reduction in effusion-synovitis with methotrexate treatment, as suggested by the literature, 9 74 participants per study group were sufficient. Our previous study reported that patients with knee OA had a mean (SD) VAS (0-100 mm) knee pain score of 50 (20) mm. 23 The sample size needed to detect a difference of 20% reduction of VAS knee pain after methotrexate treatment was 64 per arm. 20 Therefore, 100 participants in each group, allowing 20% for dropouts, would have at least 80% power to detect clinically meaningful differences between groups. Statistical Analysis Independent t tests and χ 2 tests were used to compare baseline characteristics of participants between groups. A general linear mixed model was used to evaluate changes in repeated measures (eg, VAS pain, WOMAC) in multivariable modeling between groups, with model terms for treatment, study week, and trial center. The effect of treatment was evaluated by the week × treatment interaction. Study week was treated as a fixed effect, and individual participant was incorporated as a random effect. For measures only taken at 2 time points (eg, effusion size), linear regression models omitted random intercepts and terms for time were used. Each model was adjusted for the baseline value of the corresponding outcome. Both intention-to-treat and per-protocol analyses were performed. Per-protocol analysis included patients who had achieved greater than 80% of the period of medication usage. Multiple imputation by chained equations was used to address missing data caused by loss of follow-up. The missing data patterns were nonmonotonic and consistent across groups. We used 20 chains in our multiple imputation process (m = 20). The primary analyses and subgroup analyses were conducted after multiple imputations for all participants in the intention-to-treat analysis set. In post hoc analysis, the proportions of participants achieving at least 20% and 50% improvement in VAS pain, effusion-synovitis maximal area, and effusion-synovitis volume were evaluated, which has been shown to be clinically relevant. 24 Prespecified subgroup analyses were performed to examine which subgroups may respond better to the treatment. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute), and R statistical software, version 4.0.3 (The R Project for Statistical Computing). A 2-sided P value of .05 was considered statistically significant. Results Participants A total of 278 participants were screened. Of the 215 patients who underwent randomization and were included in the intention-to-treat population ( Figure 1 ), the mean (SD) age was 60.6 (6.2) years, 191 (88.8%) were female, 54 (82.1%) had Kellgren-Lawrence grade 3 or higher, and 16 (7.4%) had severe pain (VAS ≥ 80 mm). The baseline characteristics were well-balanced between groups ( Table 1 ). A total of 175 participants completed the 52-week follow-up (86 in the methotrexate group and 79 in the placebo group); 79 participants (74%) in the methotrexate group and 81 (75%) in the placebo group adhered to greater than 80% of the intervention period. The mean (SD) dose of methotrexate was 13.8 (1.5) mg weekly in the intervention group. At baseline, 108 MRI scans were obtained in the methotrexate group and 107 in the placebo group. Follow-up MRI scans were available for 89 participants in the methotrexate group and 86 in the placebo group. There were no significant differences between the baseline characteristics of participants who completed the 52-week follow-up and those who did not ( Figure 1 ; eTable 1 in Supplement 2 ). Figure 1. Flow Diagram of Patient Enrollment, Randomization, Treatment, and Follow-Up. Open in a new tab Table 1. Participant Characteristics. Characteristic Mean (SD) Methotrexate (n = 108) Placebo (n = 107) Age, y 60.6 (6.4) 60.7 (6.0) Sex, No. (%) Female 97 (90.0) 94 (88.0) Male 11 (10.0) 13 (12.0) Body mass index a 25.7 (3.5) 25.7 (4.0) Kellgren-Lawrence score, No. (%) b 2 (Minimal OA) 22 (21.0) 16 (15.0) 3 (Moderate OA) 39 (37.1) 47 (43.9) 4 (Severe OA) 44 (41.9) 44 (41.1) Waist/hip circumference ratio 0.9 (0.2) 0.9 (0.1) Knee pain (VAS), mm 60.3 (12.2) 59.4 (13.8) Effusion-synovitis maximal area, cm 2 3.3 (2.9) 3.6 (3.6) Effusion-synovitis volume (total), cm 3 17.1 (12.5) 19.0 (14.8) WOMAC scores c Total score 986.4 (446.1) 1043.4 (457.9) Pain 209.3 (85.0) 223.2 (99.0) Stiffness 80.0 (45.7) 76.5 (46.0) Function 617.1 (341.9) 743.7 (341.1) IPFP signal intensity alteration d Standard deviation 0.1 (0) 0.1 (0) Clustering factor 0.6 (0.2) 0.6 (0.1) General health status e 49.9 (20.1) 51.8 (19.3) SF-12 32.8 (7.4) 32.9 (7.6) PHQ-9 4.8 (4.1) 4.7 (4.3) Semiquantitative MRI-detected abnormalities IPFP signal intensity score (0-3) 2.2 (0.8) 2.3 (0.7) Effusion-synovitis (sum-up score) 6.9 (2.2) 6.9 (2.2) Open in a new tab Abbreviations: IPFP, infrapatellar fat pad; MRI, magnetic resonance imaging; OA, osteoarthritis; PHQ-9, Patient Health Questionnaire–9; SF-12, Short Form–12; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. a Calculated as weight in kilograms divided by height in meters squared. b A Kellgren-Lawrence score of 2 (minimal signs of osteoarthritis) indicates definite osteophytes without reduction of the joint space; a score of 3 (moderate signs of osteoarthritis) indicates diminished joint space; and a score of 4 (severe signs of osteoarthritis) indicates greatly reduced joint space. c Scores on the pain, stiffness, and physical function subscales of the WOMAC were assessed with the use of a VAS that ranged from 0 to 100 for each item, with higher scores indicating more pain, more stiffness, and more limitation of physical function, respectively. WOMAC can range from 0 to 500 for the pain subscale, 0 to 200 for the stiffness subscale, and 0 to 1700 for the function subscale. d IPFP signal intensity alterations were defined as a discrete area of increased signal and measured using sagittal planes of fat-saturated T2-weighted MRI images or corresponding MRI sequences. e General health status was assessed with the use of a VAS that ranged from 0 to 100, with higher scores indicating better health status. Primary Outcome In the intention-to-treat analysis that was performed by a mixed effect model, adjusting for study week, trial center, and the corresponding baseline outcomes, the mean (SD) change in the VAS pain from baseline to 52 weeks was −29.5 (5.0) mm in the methotrexate group, as compared with −29.8 (5.8) mm in the placebo group (between-group difference, 0.3 mm; 95% CI, −6.7 to 7.3 mm). The mean (SD) change in the effusion-synovitis maximal area from baseline to 52 weeks was −0.2 (0.9) cm 2 in the methotrexate group, as compared with −0.3 (1.0) cm 2 in the control group (between-group difference, 0.1; 95% CI, −0.8 to 1.0) ( Table 2 ; Figure 2 ). Per-protocol analysis showed similar results (eTable 4 in Supplement 2 ). Table 2. Primary, Secondary, and Other Outcomes Over 52 Weeks in the Intention-to-Treat Population a . Outcome Mean improvement from baseline to 52 wk (95% CI) b Between-group difference in mean improvement Methotrexate (n = 108) Placebo (n = 107) Mean (95% CI) Nominal P value c Primary outcomes VAS, mm d , e −29.5 (−34.5 to −24.5) −29.8 (−35.6 to −24.0) 0.3 (−6.7 to 7.3) .93 Effusion-synovitis maximal area, cm 2 d −0.2 (−1.0 to 0.7) −0.3 (−1.2 to 0.7) 0.1 (−0.8 to 1.0) .82 Secondary outcomes IPFP signal intensity (standard deviation) −0.01 (−0.02 to 0) −0.01 (−0.02 to 0) 0.00 (−0.01 to 0.01) .80 IPFP signal intensity (clustering factor) −0.02 (−0.05 to 0.01) −0.03 (−0.06 to 0.01) 0.01 (−0.03 to 0.04) .84 WOMAC pain d , e −105.7 (−126.6 to −84.8) −107.8 (−130.1 to −85.6) 2.1 (−25.7 to 29.9) .88 WOMAC stiffness d , e −36.6 (−45.6 to −27.5) −30.6 (−40.4 to −20.9) −6.0 (−17.5 to 5.6) .31 WOMAC function d , e −317.5 (−389.7 to −245.4) −304.8 (−381.5 to −228.1) −12.7 (−109.0 to 83.5) .79 WOMAC total d , e −459.6 (−557.0 to −362.3) −441.5 (−543.4 to −339.5) −18.2 (−148.4 to 112.0) .78 OMERACT-OARSI, No. (%) 59 (54.6) 60 (56.1) NA .83 Other outcomes PHQ-9 −1.3 (−2.1 to −0.6) −1.1 (−2.0 to −0.3) −0.2 (−1.2 to 0.7) .67 SF-12 6.2 (4.4 to 8.0) 5.5 (3.7 to 7.4) 0.7 (−1.5 to 2.9) .55 General health status (VAS), mm −20.8 (−25.8 to −15.8) −18.3 (−23.4 to −13.2) −2.5 (−8.6 to 3.5) .44 Effusion-synovitis volume, cm 3 −3.3 (−5.3 to −1.2) −3.7 (−5.9 to −1.5) 0.4 (−1.7 to 2.6) .69 Effusion-synovitis score of 0-3 0 (−0.1 to 0.8) 0 (−0.2 to 0.1) 0.1 (−0.1 to 0.2) .35 BML maximal area, cm 2 −0.2 (−0.6 to 0.1) −0.0 (−0.3 to 0.3) −0.2 (−0.5 to 0.0) .09 IPFP signal intensity score of 0-3 0 (−0.1 to 0.1) −0.1 (−0.1 to 0.1) 0.0 (−0.1 to 0.1) .94 Cartilage defect, total f 0.5 (0.2 to 0.9) 0.5 (0.1 to 0.8) 0.1 (−0.2 to 0.5) .54 Concomitant medications, No. (%) Nonsteroidal anti-inflammatory drugs 22 (20.4) 24 (22.4) NA .71 Glucosamine 10 (9.3) 11 (10.3) NA .80 Antiarthritis herbal medicines 7 (6.5) 17 (15.9) NA .03 Other analgesics g 9 (8.3) 17 (15.9) NA .09 Vitamin D or calcitriol 9 (8.3) 11 (10.3) NA .62 Open in a new tab Abbreviations: BML, bone marrow lesion; IPFP, infrapatellar fat pad; NA, not applicable; OMERACT-OARSI, Outcome Measures in Rheumatology Arthritis Clinical Trials–Osteoarthritis Research Society International; PHQ-9, Patient Health Questionnaire–9; SF-12, Short Form–12; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. a Multiple imputation by chained equation was used. b Change in VAS pain and WOMAC scores results was generated from mixed models adjusted for center, week, and the corresponding baseline outcomes. c The primary end points in this hierarchy of end points were not statistically significant. Therefore, all secondary end points cannot be formally statistically tested. Nominal P values were presented for reference. d Higher values in VAS, WOMAC, and effusion-synovitis volume indicate a more severe stage of the condition. e Indices have different scales: VAS pain is 0 to 100, WOMAC pain is 0 to 500, WOMAC stiffness is 0 to 200, WOMAC function is 0 to 1700, and WOMAC total is 0 to 2400. f Sum up score. g Included opioids, prednisolone, and compound analgesics. Nonsteroidal anti-inflammatory drugs and antiarthritis herbal medicines were excluded. Figure 2. Effect of Methotrexate on Visual Analog Scale (VAS) Knee Pain Compared With Placebo. Open in a new tab Data points represent the means, and error bars represent the standard errors based on the original data without adjustment. Secondary Outcomes At 52 weeks, the mean change from baseline on the IPFP signal intensity (standard deviation and clustering factor) and WOMAC total score were comparable between groups ( Table 2 ). The mean difference between groups at 52 weeks for WOMAC pain, stiffness, and physical function were 2.1 (95% CI, −25.7 to 29.9), −6.0 (95% CI, −17.5 to 5.6), and −12.7 (95% CI, −109.0 to 83.5), respectively ( Table 2 and Figure 2 ). The response rate to therapy, as per OMERACT-OARSI criteria, was also comparable between groups (59 [54.6%] vs 60 [56.1%]; Table 2 ). Other Outcomes PHQ-9, SF-12, effusion-synovitis volume (cm 3 ), and semiquantitatively assessed total effusion-synovitis score (0-3, maximal score of subregions) improved in both groups over 52 weeks. However, these improvements were not clinically meaningful, and no statistically significant between-group differences were observed (between-group differences: −0.2, 0.7, 0.4, and 0.1, respectively) ( Table 2 ). No significant between-group differences were observed over 52 weeks for general health status, bone marrow lesion maximal area, IPFP signal intensity score, and total cartilage defect score (sum-up subregions) ( Table 2 ). Both intention-to-treat and per-protocol analyses of prespecified secondary outcomes did not show either clinically important or statistically significant differences between groups (eTables 3-6 in Supplement 2 ). Post Hoc and Subgroup Analysis Fewer participants used antiarthritis herbal medicine (7 [6.5%] vs 17 [15.9%]; nominal P = .03) and other analgesics in the methotrexate group compared with the placebo group, but the difference for other analgesics was not statistically significant ( Table 2 ). No significant differences between groups for achieving a 20% or 50% improvement in effusion-synovitis size were observed (eTable 7 in Supplement 2 ). Methotrexate had greater improvements in VAS pain, WOMAC pain, function, and total score, and general health status in participants with severe pain (VAS score ≥ 80 mm) at baseline (eTable 17 in Supplement 2 ). No effect modification was observed in other subgroup analyses stratified according to significant inflammation signs (effusion-synovitis or IPFP signal intensity score of 3), Kellgren-Lawrence grade 3 or higher at baseline, or if methotrexate maintenance dosage was 10 mg or higher weekly during the study period (eTables 9-16 in Supplement 2 ). Adverse Events Over the 52-week follow-up period, serious adverse events occurred in 1 participant (0.9%) assigned to methotrexate treatment and 4 participants (3.7%) assigned to placebo. None of these serious adverse events were considered treatment related. A total of 32 participants (29.6%) in the methotrexate group and 26 participants (24.3%) in the placebo group experienced at least 1 adverse event. There were no significant between-group differences in the frequencies of overall adverse events. Raised concentrations of liver enzymes to more than 1.5 times the upper limit of normal were found on 42 occasions (21 participants [19.4%]) in the methotrexate group and on 31 occasions (10 participants [9.3%]) in the placebo group ( P = .03) (eTable 20 in Supplement 2 ). Discussion This multicenter, randomized, placebo-controlled trial showed that during 52 weeks, methotrexate, up to 15 mg weekly, compared with placebo, did not significantly improve VAS pain or effusion-synovitis size in participants with knee OA and effusion-synovitis. These findings did not support the use of methotrexate for symptom relief or disease modification in people with inflammatory knee OA. In patients with rheumatoid arthritis, treatment with methotrexate can reduce the area of knee synovitis at the suprapatellar pouch by 35% 9 and inhibit inflammatory response in synovial tissue. 25 However, our current randomized clinical trial did not observe symptom-relieving or synovitis-reducing effects of methotrexate in inflammatory knee OA. Our findings would suggest that the type of inflammation seen in knee OA is mechanistically different from that in prototypical inflammatory arthritis. 26 Effusion-synovitis in MRI used to define inflammatory knee OA may not reflect the pathologies, such as dividing inflammatory cells or a polarized M1 state of macrophages, which are the targets of methotrexate. 26 Therefore, the approach for the treatment of inflammatory OA should be different than that of inflammatory arthritis. The findings partially align with the pilot trial by Wenham et al, 10 which did not report a significant reduction of ultrasonography-detected synovitis after methotrexate treatment. The PROMOTE trial reported that methotrexate may be effective in reducing numeric rating scale–assessed knee pain over 6 months, but not over 12 months. 11 The authors recruited and randomized 155 participants with symptomatic knee OA, but without discrimination regarding whether it was inflammatory OA. They used methotrexate dosage escalation from 10 mg to 25 mg per week, and the doses were higher than those in our current trial. The METHODS trial 12 suggested that methotrexate could provide a modest symptom-relieving effect in treating patients with hand OA and synovitis. The differences between our findings and the METHODS trial may be attributed to variations in the pathophysiologic characteristics of inflammatory hand OA and inflammatory knee OA, different dosages, or distinct ethical backgrounds. Analysis of the prespecified subgroup of patients with severe knee pain (VAS ≥ 80 mm) demonstrated that methotrexate therapy significantly improved OA symptoms, including VAS pain, WOMAC pain, function, and patients’ general health status. It should be noted that there were only 9 participants in the methotrexate group vs 7 in the placebo group with severe knee pain. Therefore, this finding does not preclude the possibility of a chance occurrence. Low-dose methotrexate is an inexpensive, effective, and widely used treatment for inflammatory conditions, and methotrexate, 10 mg to 25 mg per week, is the most commonly recommended dosage. 27 , 28 However, Chinese patients with inflammatory arthritis generally have a therapeutic response to low-dose methotrexate, up to 15 mg weekly. 15 Methotrexate, 15 mg per week, is routinely recommended for the treatment of rheumatoid arthritis in China, when considering the balance between safety and efficacy. 29 In Japan, methotrexate was approved as a first-line drug for rheumatoid arthritis treatment with a primarily targeted dose of 10 mg to 12 mg per week and a maximum dose of 16 mg per week by the Japan College of Rheumatology. 30 As White individuals have, on average, greater body surface areas than Asian individuals, which significantly influences concentration and clearance of methotrexate, 31 it is reasonable to use methotrexate, 15 mg per week, in Asian individuals and methotrexate, 20 mg to 25 mg per week, in White individuals. Therefore, our clinical trial administered methotrexate, 15 mg per week, after dose escalation. Methotrexate is generally safe and well tolerated, as no serious adverse events were considered treatment-related, and nearly all the adverse events were mild or moderate, which aligns with previous trials. 12 , 32 Gastrointestinal reactions and abnormal laboratory test results were the most common adverse events of methotrexate, but the gastrointestinal reactions were balanced evenly between the 2 study groups. Although abnormal laboratory test results, specifically abnormal liver function, occurred more frequently in the methotrexate group than in the placebo group, none of these abnormal test results led to serious adverse events. Limitations Our study had several potential limitations. First, this study was conducted during COVID-19 shutdowns in China, which delayed the recruitment period. This might also increase the loss of follow-up and nonadherence rates; however, the loss to follow-up was acceptable (17% in the methotrexate group and 20% in the placebo group), and 74% of participants in the methotrexate group and 75% in the placebo group adhered to more than 80% of the intervention period. The rates of loss to follow-up and nonadherence with medicine-taking were evenly distributed among the 2 groups, and there were no notable variations in demographic characteristics between participants who completed and those who dropped out. Second, the trial population consisted predominantly of female patients, and the limited representation of racial and ethnic diversity could potentially impact the generalizability of our findings. Third, implementing multiple imputation by chained equations when data are not missing at random could result in biased estimates. However, the sensitivity analysis using unimputed data yielded comparable results, indicating that the findings are robust. Finally, the relatively small number of participants in each subgroup may have limited the ability to detect significant benefits. Conclusions In this randomized clinical trial, we found that, compared to placebo, low-dose methotrexate did not relieve pain or reduce the size of effusion-synovitis over 52 weeks in patients with inflammatory knee OA. Further studies are required to confirm if methotrexate has an effect on inflammatory knee OA with severe knee pain. Supplement 1. Trial Protocol jamainternmed-e251359-s001.pdf (1.2MB, pdf) Supplement 2. eMethods eFigure 1. Effect of methotrexate on WOMAC assessments compared with placebo eFigure 2. Mean changes in general health status, PHQ-9 and SF-12 during the 52-week period (ITT population) eTable 1. Baseline characteristics of those completed and dropouts eTable 2. Additional baseline characteristics eTable 3. Intention-to-treat analysis of changes in outcomes over 52 weeks using unimputed data eTable 4. Per-protocol analysis of changes in outcomes over 52 weeks eTable 5. Detailed changes for outcomes using mixed model after multiple imputation (ITT) eTable 6. Detailed changes for outcomes using mixed model after multiple imputation (PP) eTable 7. Post-hoc analysis (ITT) eTable 8. Adverse events eTable 9. Subgroup analysis by semi-quantitatively measured total effusion-synovitis score (= 3) eTable 10. Subgroup analysis by semi-quantitatively measured total effusion-synovitis score (< 3) eTable 11. Subgroup analysis by semi-quantitatively measured baseline IPFP signal intensity score (= 3) eTable 12. Subgroup analysis by semi-quantitatively measured baseline IPFP signal intensity score (< 3) eTable 13. Subgroup analysis by baseline KL grade (ITT, Baseline KL < 3) eTable 14. Subgroup analysis by baseline KL grade (ITT, Baseline KL = 2) eTable 15. Subgroup analysis by methotrexate maintenance dosage (≥ 10 mg per week) eTable 16. Subgroup analysis by methotrexate maintenance dosage (< 10 mg per week) eTable 17. Subgroup analysis by baseline VAS pain (Baseline VAS ≥ 80) eTable 18. Subgroup analysis by baseline VAS pain (Baseline VAS < 80) eTable 19. Primary and secondary outcomes at 52 weeks by using unimputed data (ITT) eTable 20 Adverse events that only considered treatment related eTable 21. Reasons for discontinuation eTable 22. Representativeness of study participants eReferences jamainternmed-e251359-s002.pdf (2.2MB, pdf) Supplement 3. Data Sharing Statement jamainternmed-e251359-s003.pdf (16.4KB, pdf) References 1. Duong V, Oo WM, Ding C, Culvenor AG, Hunter DJ. Evaluation and treatment of knee pain: a review. JAMA. 2023;330(16):1568-1580. doi: 10.1001/jama.2023.19675 [ DOI ] [ PubMed ] [ Google Scholar ] 2. Jin X, Jones G, Cicuttini F, et al. 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Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-355. doi: 10.1016/S0140-6736(16)30363-4 [ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Supplement 1. Trial Protocol jamainternmed-e251359-s001.pdf (1.2MB, pdf) Supplement 2. eMethods eFigure 1. Effect of methotrexate on WOMAC assessments compared with placebo eFigure 2. Mean changes in general health status, PHQ-9 and SF-12 during the 52-week period (ITT population) eTable 1. Baseline characteristics of those completed and dropouts eTable 2. Additional baseline characteristics eTable 3. Intention-to-treat analysis of changes in outcomes over 52 weeks using unimputed data eTable 4. Per-protocol analysis of changes in outcomes over 52 weeks eTable 5. Detailed changes for outcomes using mixed model after multiple imputation (ITT) eTable 6. Detailed changes for outcomes using mixed model after multiple imputation (PP) eTable 7. Post-hoc analysis (ITT) eTable 8. Adverse events eTable 9. Subgroup analysis by semi-quantitatively measured total effusion-synovitis score (= 3) eTable 10. Subgroup analysis by semi-quantitatively measured total effusion-synovitis score (< 3) eTable 11. Subgroup analysis by semi-quantitatively measured baseline IPFP signal intensity score (= 3) eTable 12. Subgroup analysis by semi-quantitatively measured baseline IPFP signal intensity score (< 3) eTable 13. Subgroup analysis by baseline KL grade (ITT, Baseline KL < 3) eTable 14. Subgroup analysis by baseline KL grade (ITT, Baseline KL = 2) eTable 15. Subgroup analysis by methotrexate maintenance dosage (≥ 10 mg per week) eTable 16. Subgroup analysis by methotrexate maintenance dosage (< 10 mg per week) eTable 17. Subgroup analysis by baseline VAS pain (Baseline VAS ≥ 80) eTable 18. Subgroup analysis by baseline VAS pain (Baseline VAS < 80) eTable 19. Primary and secondary outcomes at 52 weeks by using unimputed data (ITT) eTable 20 Adverse events that only considered treatment related eTable 21. Reasons for discontinuation eTable 22. Representativeness of study participants eReferences jamainternmed-e251359-s002.pdf (2.2MB, pdf) Supplement 3. Data Sharing Statement jamainternmed-e251359-s003.pdf (16.4KB, pdf) Articles from JAMA Internal Medicine are provided here courtesy of American Medical Association ACTIONS View on publisher site Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

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