Maryam Obaid

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation affecting the synovial tissues of joints, cartilage, bones, and occasionally extra-articular surfaces like the heart, lungs, digestive, and nervous systems. Globally, RA affects approximately 18.5 million people, significantly impacting life expectancy and quality of life, with a predicted increase in incident cases by 2040^1,2. Additionally, RA imposes a substantial public health burden, with mean all-cause direct costs ranging from $12,509 to $20,919 per patient annually³. Despite the overall cumulative burden on life, treatment options for RA are limited. Currently, NSAIDs offer temporary relief for RA-associated pain, while disease-modifying agents (DMARDs) pose risks of adverse effects such as gastric ulcers, hypertension, and renal abnormalities, limiting their use. Resveratrol (3,5,4′-trihydroxy trans-stilbene), a naturally occurring polyphenol with anti-inflammatory, anticancer, and antioxidant properties, appears to have potential in the management of RA⁴.

Objective: The present study investigates the molecular interaction of resveratrol with molecules implicated in RA pathogenesis and highlights its potential applications for RA therapy.

Search Methods: A search to identify in vitro, animal, and human studies investigating resveratrol in the management of RA was performed using the following keywords: “resveratrol,” “rheumatoid arthritis,” “autoimmune disease,” “inflammatory condition,” and “rheumatoid arthritis therapy.” The search included articles and reviews published from 2018 to 2024.

Results: The analyzed articles show that resveratrol reduces oxidative stress and inflammation, both of which contribute to RA pathogenesis. In animal models, resveratrol treatment confirmed reductions in arthritic indices such as paw swelling and redness. In vitro analyses demonstrated reversed increases in malondialdehyde levels and decreases in superoxide dismutase levels, indicating resveratrol’s ability to combat oxidative stress^4,5. Plasma serum concentrations of proinflammatory cytokines were also reduced through regulation of the MAPK pathway and angiogenesis via HIF-1α regulation⁴. The main resveratrol activity is exerted through activation of the SIRT1/Nrf2-ARE pathway, leading to reduced cell proliferation and increased apoptosis in fibroblast-like synoviocytes (FLS), while suppressing FLS migration and invasion⁵. Resveratrol also promoted cell cycle arrest, upregulated p53, and downregulated cyclin B, ultimately enhancing apoptosis in RA-FLS⁶. Resveratrol’s limited bioavailability poses a challenge, as only trace amounts remain in the serum after a few hours. Efforts have been made to combine resveratrol with bioenhancers like piperine to improve bioavailability and achieve better clinical outcomes in RA patients⁷. Other applications include delivery systems such as resveratrol-loaded PLGA microspheres, which offer potential for controlled, sustained release and cartilage regeneration⁸. A clinical trial indicates that resveratrol administration alongside conventional antirheumatic drugs significantly improves clinical and biochemical markers in RA patients⁹.

Conclusion: Resveratrol offers advantages for managing rheumatoid arthritis, serving as an anti-inflammatory and antioxidant agent. This opens the door for its use as a supplement alongside standard medications and for local injections. However, dosing and formulation remain significant issues. Future research should focus on developing stable formulations with effective bioavailability.

Works Cited:

1. Radu A-F, Bungau SG. Management of Rheumatoid Arthritis: An Overview. Cells. 2021; 10(11):2857. https://doi.org/10.3390/cells10112857
2. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. Journal of Autoimmunity. 2020; 110:102400. doi: 10.1016/j.jaut.2019.102400
3. Shi G, Liao X, Lin Z, et al. Estimation of the global prevalence, incidence, years lived with disability of rheumatoid arthritis in 2019 and forecasted incidence in 2040: results from the Global Burden of Disease Study 2019. Clin Rheumatol. 2023;42(9):2297-2309. doi:10.1007/s10067-023-06628-2
4. Yang G, Chang CC, Yang Y, et al. Resveratrol alleviates rheumatoid arthritis via reducing ROS and inflammation, inhibiting MAPK signaling pathways, and suppressing angiogenesis. J Agric Food Chem. 2018;66(49):12953-12960. doi:10.1021/acs.jafc.8b05047
5. Wang G, Xie X, Yuan L, et al. Resveratrol ameliorates rheumatoid arthritis via activation of SIRT1‐Nrf2 signaling pathway. BioFactors. 2020;46(3):441-453. doi:10.1002/biof.1599
6. Li S, Du J, Gan H, et al. Resveratrol promotes apoptosis and G2/M cell cycle arrest of fibroblast-like synoviocytes in rheumatoid arthritis through regulation of autophagy and the serine-threonine kinase-p53 axis. Arch Med Sci. 2021;20(1):280-288. doi:10.5114/aoms/119022
7. El-Ghazaly MA, Fadel NA, Abdel-Naby DH, Abd El-Rehim HA, Zaki HF, Kenawy SA. Potential anti-inflammatory action of resveratrol and piperine in adjuvant-induced arthritis: Effect on pro-inflammatory cytokines and oxidative stress biomarkers. The Egyptian Rheumatologist. 2020;42(1):71-77. doi:10.1016/j.ejr.2019.08.003
8. Wang X, Li X, Duffy P, et al. Resveratrol‐loaded poly(d , l ‐lactide‐ co ‐glycolide) microspheres integrated in a hyaluronic acid injectable hydrogel for cartilage regeneration. Advanced NanoBiomed Research. 2022;2(1):2100070. doi:10.1002/anbr.202100070
9. Khojah HM, Ahmed S, Abdel-Rahman MS, Elhakeim EH. Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. Clin Rheumatol. 2018;37(8):2035-2042. doi:10.1007/s10067-018-4080-8