Flavia M. Cicuttini

Modern rheumatology • October 19, 2024

Ambrish Singh, Alison Venn, Leigh Blizzard, Brooklyn Fraser, Graeme Jones, John Burgess, Venkat Parameswaran, Lyn March, Flavia Cicuttini, Changhai Ding, Benny Antony

Objective: To examine associations between osteoarthritis (OA)-related biochemical markers and knee symptoms in middle-aged adults over 10-13 year follow-up. Methods: Blood samples were collected during the Childhood Determinants of Adult Health (CDAH)-1 study (2004-06) and follow-up at CDAH-3. Serum samples from baseline (n=156) and follow-up (n=167) were analyzed for cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-3, and hyaluronan (HA) using enzyme-linked immunosorbent assays. Knee symptoms were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale at follow-up. Zero-inflated Poisson regression models adjusted for age, sex, and body mass index were used for analysis. Results: Significant associations were observed between COMP, MMP-3, and HA with knee pain and WOMAC-total score at follow-up. Baseline MMP-3 [ratio of means (RoM): 1.013; 95% CI: 1.006, 1.020], cumulative COMP (baseline + follow-up) [RoM: 1.022; 95% CI: 1.011, 1.033], and increased HA levels over time [RoM: 1.014; 95% CI: 1.007, 1.020] were positively associated with knee pain after 10-13 years. Conclusions: Cumulative COMP, baseline MMP-3, and changes in HA were associated with knee pain over a a 10-13 year follow-up. These markers may help predict future knee symptoms in middle-aged adults.

JAMA Internal Medicine • June 02, 2025

Zhaohua Zhu, Qinghong Yu, Xiaomei Leng, Jianhua Xu, Limin Ren, Kun Wang, Cibo Huang, Yunfeng Pan, Yi Zhao, Tianwang Li, Yifang Mei, Meihua Guan, Xiaoxia Li, Zhiyi Zhang, Jing Wu, Yingjuan Chen, Yuan Qu, Xiaotong Zhu, Qiuju Liao, Zhe Wang, Zetao Liao, Yang Xi, Weiming Deng, Kang Wang, Tingting Zhu, Yuping Zhang, Lixia Gao, Xiaoni Zhou, Weiyu Han, Guangfeng Ruan, Yan Zhang, Peihua Cao, Peichun Gao, Haowei Chen, Qin Dang, Flavia Cicuttini, David Hunter, Zhanguo Li, Xiaofeng Zeng, Changhai Ding

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. To examine whether methotrexate has symptom-relieving and disease-modifying effects for participants with knee OA and effusion-synovitis. 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. Participants were randomly assigned (1:1) to receive methotrexate, up to 15 mg weekly, or placebo using block randomization, stratified by study site. 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. 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. 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. ClinicalTrials.gov Identifier: NCT03815448.

Jama • April 24, 2025

Feng Pan, Yuanyuan Wang, Yuan Lim, Donna Urquhart, Mahnuma Estee, Anita Wluka, Rory Wolfe, Flavia Cicuttini

Preclinical and preliminary human evidence suggests that metformin, a first-line treatment for type 2 diabetes, reduces inflammation, preserves cartilage, and improves knee pain in knee osteoarthritis. To evaluate the effects of metformin on knee pain at 6 months in participants with symptomatic knee osteoarthritis and overweight or obesity. Community-based randomized, parallel-group, double-blind, placebo-controlled clinical trial that used telemedicine to recruit and follow up participants remotely. Individuals with knee pain for 6 months or longer, a pain score greater than 40 mm on a 100-mm visual analog scale (VAS), and body mass index of 25 or higher were recruited from the community through local and social media advertisements in Victoria, Australia, between June 16, 2021, and August 1, 2023. Final follow-up occurred on February 8, 2024. Participants were randomly assigned to receive either oral metformin, 2000 mg/d (n = 54), or identical placebo (n = 53) for 6 months. The primary outcome was change in knee pain, measured using a 100-mm VAS (score range, 0-100; 100 = worst; minimum clinically important difference = 15) at 6 months. Of 225 participants assessed for eligibility, 107 (48%) were randomized (mean age, 58.8 [SD, 9.5] years; 68% female) and assigned to receive metformin or placebo. Eighty-eight participants (82%) completed the trial. At 6 months, the mean change in VAS pain was -31.3 mm in the metformin group and -18.9 mm in the placebo group (between-group difference, -11.4 mm; 95% CI, -20.1 to -2.6 mm; P = .01), corresponding to an effect size (standardized mean difference) of 0.43 (95% CI, 0.02-0.83). The most common adverse events were diarrhea (8 [15%] in the metformin group and 4 [8%] in the placebo group) and abdominal discomfort (7 [13%] in the metformin group and 5 [9%] in the placebo group). These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity. Because of the modest sample size, confirmation in a larger clinical trial is warranted. ANZCTR Identifier: ACTRN12621000710820.

Brain, Behavior, And Immunity • January 16, 2025

Jialiu Fang, Zemene Kifle, Jing Tian, Silvana Bettiol, Flavia Cicuttini, Graeme Jones, Feng Pan

Evidence suggests that pathogens may influence pain perception and regulation; however, no study has explored the relationship between serological evidence of infection and multisite chronic musculoskeletal pain. Therefore, this study aimed to investigate the association between serological evidence of infection and multisite chronic musculoskeletal pain. Participants (n = 6,814; mean [SD]age, 56.5[8.2] years; females [52.9 %]) in the UK Biobank were included. Multiplex serology panel measuring serum immunoglobulin G antibody levels against 20 infectious agents was performed at baseline. Chronic pain (≥3 months) in the knee, neck/shoulder, hip, back, or 'all over the body' was assessed at baseline and follow-up. Participants were grouped by number of chronic pain sites: no chronic pain, chronic pain in 1-2 sites, or ≥3 sites. Multinomial logistic regression and mixed-effect multinomial logistic regression models were used for the analyses. The seroprevalences of serologically detected infections across the 20 agents ranged from 0.2 % to 95.4 %. In multivariable analyses, serological evidence of infection with Epstein-Barr Virus (EBV), Human T-Cell Lymphotropic Virus Type-1 (HTLV-1), and Chlamydia Trachomatis was cross-sectionally associated with chronic pain in ≥3 sites compared to those without chronic pain. In longitudinal analyses, EBV [relative risk ratio (RRR) = 2.18, 95 %CI:1.17 - 4.05] and Chlamydia Trachomatis [RRR = 1.38, 95 %CI:1.09 - 1.74] were also associated with chronic pain in ≥3 sites. Additionally, serological evidence of single and multiple infections was associated with chronic pain in ≥3 sites, but not in 1-2 sites. Collectively, serological evidence of infection with EBV and Chlamydia Trachomatis is associated with multisite chronic musculoskeletal pain. These findings suggest that infectious agents may play a role in the pathogenesis of widespread chronic pain.

Maturitas • September 04, 2024

Mengjie Zeng, Susan Davis, Flavia Cicuttini, Angus Franks, John Mcneil, Yuanyuan Wang

Objective: To examine whether low circulating sex steroid concentrations are associated with the incidence of knee and hip replacement for osteoarthritis in community-dwelling older women. Methods: This prospective cohort study examined 5535 Australian women recruited into the Aspirin in Reducing Events in the Elderly (ASPREE) trial, aged ≥70 years, not taking medications affecting sex steroid concentrations, and with sex steroid concentrations measured by liquid chromatography-tandem mass spectrometry. Methods: The incidence of knee and hip replacement for osteoarthritis was determined by hospitalisations for knee and hip surgical procedures where osteoarthritis was recorded as the indication. Results: With a mean follow-up of 3.9 (SD 1.4) years, 311 women underwent knee replacement and 242 underwent hip replacement. A greater incidence of knee replacement was observed in women with the lowest quartile concentrations of oestrone (HR 1.35, 95 % CI 1.04-1.75, p = 0.03) and testosterone (HR 1.35, 95 % CI 1.05-1.72, p = 0.02) compared with quartiles 2 to 4, after adjusting for age, body mass index, socioeconomic status, smoking, alcohol consumption, and comorbidities. A greater likelihood of hip replacement was seen for women with the lowest quartile concentrations of dehydroepiandrosterone compared with quartiles 2 to 4 (HR 1.37, 95 % CI 1.03-1.82, p = 0.03). Conclusions: Low concentrations of endogenous sex steroids were associated with a greater likelihood of lower-limb joint replacement for osteoarthritis in community-based women aged 70 years or older. These findings suggest sex steroids contribute to musculoskeletal health in later life, although the mechanisms by which sex steroids might influence joint replacement remain unclear. Results: gov NCT01038583. International Standard Randomized Controlled Trial Number Register ISRCTN83772183.