Walking for gout prevention: what are potential mechanisms and practical applications?

This editorial refers to ‘Genetic susceptibility, walking activity, and the risk of incident gout’, by Wu et al. 2025, doi: 10.1093/rheumatology/keaf690 Gout is one of the most common inflammatory joint diseases in adults. It is characterized by debilitating episodes of painful arthritis known as gout flares. Gout exerts a negative impact on health-related quality of life (HRQoL), work productivity and healthcare expenditures. Pathophysiologically, hyperuricemia is the primary driver of gout, leading to the deposition of monosodium urate (MSU) crystals in articular and periarticular tissues, which subsequently triggers acute inflammatory responses and, when left untreated, joint destruction [1]. The aetiology of hyperuricemia is multifactorial, involving both the non-modifiable genetic predispositions and modifiable lifestyle factors. While genetic susceptibility cannot be altered, lifestyle interventions remain a viable target for primary prevention or delaying gout onset. In this context, the study by Wu et al. featured in the current issue of Rheumatology, provides evidence suggesting that increased walking activity may attenuate the risk of incident gout, even among individuals with high genetic susceptibility [2]. However, the specific mechanistic pathways underlying this association have not been fully elucidated. In their retrospective cohort study, Wu et al. utilized data from the UK Biobank to examine the relationship between physical activity and incident gout [2]. The study population was restricted to people of European ancestry for whom both a polygenic risk score (PRS) and objective physical activity data (measured via wrist-worn accelerometers) were available. Rather than using self-reported data, the study used accelerometry to measure walking activity and International Classification of Diseases, 10th Revision (ICD-10) codes to define incident gout. The use of objective measurements helps minimizing the recall bias often inherent in lifestyle studies. The results demonstrate an inverse relationship between walking volume and gout incidence, which was most pronounced among those in the high genetic risk stratum. Compared with people with low walking volume, those characterized by moderate walking volume exhibited a hazard ratio (HR) of 0.68 (95% CI, 0.53–0.87), while those with high walking volume showed a sharper reduction in risk, with an HR of 0.55 (95% CI, 0.40–0.75). Notably, these risk models remained statistically significant after adjusting for dietary patterns, alcohol consumption and various demographic factors, thereby underscoring the reliability of their findings. Similar inverse associations between high walking intensity and gout risk were observed across all PRS strata. However, it is important to note that the models did not adjust for baseline serum urate levels or metabolic indices, as these data were unavailable in the dataset. While the observed statistical association aligns with other epidemiological surveys suggesting the benefits of physical activity, the underlying drivers of this correlation warrant further exploration [3]. There are multiple potential explanations for why walking appears to offer some protection against incident gout (Fig. 1). It must be emphasized, however, that these pathways remain speculative, as studies providing direct supporting evidence are currently lacking. Potential effects of walking activity on different stages of gout development A primary explanation for these findings is that walking activity serves as a surrogate for an overall healthy lifestyle. Individuals characterized by high walking volume and intensity are likely to be more health-conscious and may engage in health behaviours that extend beyond walking [4]. Furthermore, the data utilized by Wu et al. were extracted from a subset of those who regularly wore a wrist accelerometer for a designated period [2]. This methodology introduces a potential selection bias, as people willing to participate in such active monitoring often represent a more health-motivated demographic than the general population. Therefore, walking activity may not be the only protective factor but rather a surrogate marker for a cluster of factors that are known to be associated with a lower serum urate level and risk of incident gout [5]. In this scenario, individually recommending regular walking as an intervention to specifically prevent gout in high-risk populations may not yet be appropriate without additional evidence of a direct causal link. A more direct physiological explanation for the association between high walking activity and gout prevention remains largely unexplored. Theoretically, walking activity could modulate the pathogenesis of gout by influencing two critical stages of the disease: the formation of MSU crystals within the joints and the subsequent inflammatory response to those crystals. Beyond its metabolic benefits, walking activity may exert a localized effect on the joint microenvironment by increasing the solubility of MSU crystals through several mechanisms. First, regular joint movement enhances the flow of synovial fluid, facilitating an exchange of urate between the joint space and the vascular system. This process may prevent synovial fluid stagnation and supersaturation of urate, which helps mitigate crystal formation [6]. Furthermore, the mechanical action of walking can lead to increases in intra-articular temperature and pH. Since the solubility of uric acid is dependent on these variables, an elevation in temperature and alkalinity can raise the saturation point of uric acid, making the joint microenvironment less favourable to the formation of MSU crystals [7]. The health of the articular cartilage is another factor in the MSU crystal formation process. Insights from osteoarthritis research suggest that regular joint movement is vital for maintaining cartilage integrity by enhancing passive diffusion of nutrients (e.g. glucose, oxygen) from the synovial fluid. Mechanical loading, inherent in activities like walking and running, is essential for the active transport of high-molecular-weight molecules, such as growth factors and enzymes, into the cartilage matrix [8]. In the context of gout, MSU crystal deposition occurs predominantly on the cartilage surface. It has been proposed that damaged or degenerated cartilage is more prone to crystal formation due to the exposure of collagen structure of the superficial tangential layer that act as nucleation templates [9]. Consequently, the high walking activity observed in the study by Wu et al. may be associated with healthier cartilage that is structurally less predisposed to crystal deposition. The inflammatory response to deposited MSU crystals represents the final step before the first clinical manifestation of gout. There is some evidence suggesting that regular physical activity may modulate this response by suppressing several mediators known to be involved in the initiation and escalation of MSU crystal-induced inflammation [10]. In an animal model, low-to-moderate exercise was associated with a decrease in interleukin-1β (IL-1β) at the site of MSU crystal injection. Furthermore, low-to-moderate exercise appeared to induce systemic down-regulation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, suppressing Toll-like receptor 2 (TLR2) expression on peripheral neutrophils and reducing serum levels of neutrophilic chemokine C-X-C motif chemokine ligand 2 (CXCL2), compared with non-exercise controls [10]. In conclusion, while evidence directly linking walking to the prevention of gout in the general population remains limited, maintaining an active lifestyle that incorporates regular walking is a low-risk intervention with extensive known health benefits. However, it is essential to distinguish these preventive measures from the management of established gout. For people with gout diagnosis, the clinical priority shifts from mitigation of inflammation and crystal formation to urate-lowering therapy aimed at inducing crystal dissolution; a therapeutic goal that cannot be achieved through lifestyle prescription alone. Thus, while walking serves as a valuable adjunct for general health, it should not supersede pharmacological intervention necessary for successful control of established gout. No new data were generated or analysed in support of this manuscript. No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.