Association between oxidative balance score and rheumatoid arthritis in female: a cross-sectional study

Rheumatoid arthritis (RA) is an autoimmune disease that symmetrically affects numerous joints, predominantly the hand and foot joints [1]. As RA progresses, patients become increasingly intolerant of joint pain and experience loss of joint mobility, joint deformation and even disability, severely diminishing the quality of life [2]. According to the Global Burden of Diseases, Injuries, and Risk Factors Study, an estimated 17.6 million people worldwide were affected by RA. Remarkably, women were disproportionately affected, with their prevalence being roughly 2.45 times higher than men post age-standardization [3]. Unfortunately, current therapeutic approaches cannot cure RA, patients can only be given non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs to mitigate symptoms and slow the progression of RA [4]. Advanced cases with severe joint stiffness and dislocation might necessitate joint replacement surgery, which may require multiple operations. Clearly, addressing the challenges of RA remains a pressing issue.

Notably, oxidative stress has been identified as a pivotal factor in the pathology of RA [5]. Reactive oxygen species (ROS) are generated in the course of RA immune response [6], among which hydrogen peroxide inhibits proteoglycan synthesis and hydroxyl radical accelerates proteoglycan degradation [7]. In addition, hydroxyl radicals can interact with chloride ions to produce hypochlorous acid [5], which also restrains proteoglycan synthesis by activating matrix metalloproteinases, thus mediating cartilage repair disorders and cartilage dysfunction [7, 8]. In recent years, a growing number of studies emphasized the effects of antioxidants and pro-oxidants on RA, with daily diet and lifestyle taking center stage. Fruits and vegetables rich in vitamins and polyphenol compounds, as well as olive oil rich in omega-3 fatty acids and tocopherols, are known for their antioxidant nature, removing or inhibiting free radicals, and can significantly reduce the risk of RA [9, 10]. On the contrary, smoking, recognized for its pro-oxidative attribute due to releasing free radicals [6], significantly increases the risk of RA either actively or passively [11, 12]. Additionally, fat accumulation is also closely related to oxidative stress, and immoderate caloric intake induces ROS production [13]. Hence, Obesity is associated with an elevated risk of developing RA [14, 15].

The oxidative balance score (OBS) serves as a novel scoring system to evaluate the antioxidant/oxidative level, which represents the comprehensive impact of 20 factors on the bodily oxidative stress state. Higher OBS indicates elevated body antioxidant levels. Previous studies have shown that OBS is inversely associated with multiple diseases, such as neuropsychiatric diseases, metabolic diseases and cardiovascular diseases. Individuals with higher OBS exhibited fewer depressive symptoms [16], increased femur bone density, and reduced osteoporosis risk in postmenopausal women [17]. Lifestyle components like weight management, balanced diet, and regular exercise, are all known antioxidants, leading to high OBS and decreasing diabetes risk [18]. Subsequent research from the same team revealed a negative correlation between OBS and metabolic syndrome [19], further verifying the potential protective role of OBS against metabolic diseases. Besides, there existed a negative link between OBS and ischemic heart disease, with each OBS unit increasing reducing the risk by 18% [20]. According to the protective effect of high OBS on many diseases, we speculate that OBS [including Total OBS (TOBS), Dietary OBS (DOBS) and lifestyle OBS (LOBS)] may also exhibit a negative correlation with RA in female population. And National Health and Nutrition Examination Survey (NHANES) data as well as multiple statistical techniques were utilized to test this hypothesis.

Since RA is more common in women, we conducted this cross-sectional study using 597 RA patients and 7622 participants without RA from the NHANES database for this gender. This study pointed out that the higher the OBS of the female population, the lower the prevalence of RA, signifying a negative correlation between all three kinds of OBS and RA. In a fully adjusted model that accounted for all confounders, for each unit increase, the risk of RA was decreased by 3.2% in TOBS, 2.5% in DOBS, and 13.9% in LOBS. In addition, subgroup analyses results suggested the subgroups exhibited no significant modification effect of the negative correlation between OBS and RA, except for the PIR subgroup in LOBS. Moreover, a smooth curve fitting model was established and further verified the negative linear relationship between OBS and RA. Collectively, the results indicated that OBS, which represents the bodily oxidative stress state, is a simple and effective tool for the epidemiological study of RA.

RA is a complex disease characterized by diverse progression rates and varied treatment responses. The present-day assessment of its activity and severity is rooted in a blend of clinical examinations and laboratory analyses, which guide treatment strategies. The employment of biomarkers has been eyed as a potential avenue for delivering a more precise, objective evaluation of disease states. The academic arena has seen a burgeoning interest in biomarkers pertinent to arthritis risk, development, and prognosis. Slama et al. [32] affirmed the efficacy of both the Clinical Disease Activity Index and the Simplified Disease Activity Index (SDAI) in appraising disease activity among RA patients within the Moroccan demographic. Diving into a novel approach, González-Álvaro et al. [33] devised a straightforward and easily accessible index, termed Hospital Universitario La Princesa Index (HUPI), to measure RA disease activity. They advocate that HUPI eclipses SDAI when it comes to distinguishing between low-to-moderate disease activity, and it surpasses DAS28 in pinpointing clinical remission. On a different note, Xu et al. [34] orchestrated a multicentric retrospective exploration, unveiling that when pitted against the neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, and platelet/lymphocyte ratio, the Systemic Inflammatory Response Index emerges as a promising new biomarker. This index might ease the diagnostic journey and mirror disease activity in RA patients, with the potential to predict the emergence of RA-associated interstitial lung disease and tumors. Moreover, our prior investigation discerned a non-linear positive correlation between the Triglyceride Glucose Index, a biomarker indicative of insulin resistance, and arthritis [35]. Yet, the scholarly domain hasn’t delved into exploring the potential interplay between OBS, a novel accessible biomarker for oxidative stress, and RA.

To our knowledge, this investigation pioneers a population-based study aimed at discerning the relationship between OBS and RA. Historically, a multitude of studies has explored the nexus between OBS and diverse ailments, employing a spectrum of epidemiological approaches across varied demographic cohorts. A comprehensive cross-sectional study by Liu et al. [36] encompassing 18,716 American participants, unearthed a significant and stable negative non-linear relationship between OBS, DOBS, LOBS, and depression (P for non-linear < 0.05), with a more pronounced correlation in women. Lei et al. [37] surveyed 6,300 individuals, unveiling that OBS bore a negative correlation with sleep disturbance (OR = 0.97; 95%CI = 0.94 to 0.99), and a positive one with sleep duration (mean difference = 0.02, 95%CI = 0.01 to 0.03), particularly among women below 50 (P < 0.001). Further afield, Yeo et al. [38] studied 5,807 Korean subjects, finding that higher OBS corresponded with significantly smaller neck circumferences, indicative of a possible oxidative imbalance mirrored in central obesity. Song et al. [39] investigated 1,745 American seniors, and discerned a positive correlation between OBS and cognitive function, with each one-unit increase in OBS associated with a 0.03 point increase in global cognitive function scores in a fully adjusted model, and that albumin, uric acid, and serum 25 (OH)-D concentrations potentially mediated this association. Shifting the focus to bone health, Shahriarpour et al. [40] conducted a study on 151 postmenopausal Iranian women aged between 50 and 85 years, revealing that a higher OBS, signifying a dominance of antioxidant exposures, was associated with a reduced risk of lumbar spine osteoporosis. In a similar vein, Cho et al. [41] determined that a higher OBS significantly correlated with a lower risk of non-alcoholic fatty liver disease incidence in 10,030 Korean middle-aged and elderly individuals. Prospective cohort studies by Son et al. [42] and Lee et al. [43] respectively unearthed that higher OBS was linked with a lower risk of chronic kidney disease [hazard ratio (HR) = 0.94, 95%CI = 0.91 to 0.97) and new-onset hypertension(HR = 0.94, 95%CI = 0.92 to 0.97]. Liu et al. [44] found that TOBS and DOBS levels were positively correlated with vascular endothelial function, revealing another link between OBS and cardiovascular disease. Qu et al. [45] illustrated a negative linear association between OBS and periodontitis among US adults, and the risk of periodontitis was reduced by 11% for every 1 unit increase in OBS, proposing OBS as a viable biomarker for periodontitis evaluation. The accruing body of evidence underscores the potential of OBS in evaluating a gamut of diseases, laying a robust foundation for our trailblazing study aimed at elucidating the relationship between OBS and RA.

Beyond identifying a robust association between OBS and RA, an intriguing aspect of our analysis revealed that PIR exerted a modulatory effect on the relationship between LOBS and RA. Specifically, this interaction emerged because the association between LOBS and RA did not hold significance within the cohort with high PIR. This observation aligns with previous research investigating lifestyle factors across different income brackets. For instance, Birch et al. [46] highlighted that higher income brackets might mitigate the adverse health effects of smoking, indicating that economic advantage could lessen vulnerability to such lifestyle risks. While Lewer et al. [47] found a propensity for excessive alcohol consumption in lower socio-economic groups, correlating with a higher susceptibility to alcohol-related health issues. Moreover, a prospective study confirmed the link between higher income levels and healthier lifestyle choices, ultimately leading to a diminished risk of negative health outcomes [48]. Consequently, it is plausible that populations with higher incomes possess greater means and opportunities for maintaining healthful lifestyles, which not only improves baseline health but also decreases RA risk. This scenario likely accounts for the diluted influence of antioxidant-rich lifestyles on RA among those with high PIR, manifesting as a non-significant LOBS-RA association in these groups.

The underlying mechanisms driving the association between OBS and RA remain unclear. The link between oxidative stress and RA is intricate and multi-faceted. The following points can help illuminate the latent mechanisms between oxidative stress and RA. Firstly, under normal circumstances, the body also naturally produces free radicals as well as ROS. Oxidative stress arises with an excess of free radicals or ROS, which can attack cellular lipids, proteins and DNA, conducing to cellular damage and inflammatory responses. In RA patients, joint synovial cells and chondrocytes may produce excessive free radicals, resulting in tissue destruction and inflammation. An observational study conducted by Ogul et al. [49] suggested that malondialdehyde, a strong marker of free oxygen radicals, was notably elevated in RA patients. Khojah H. M. et al. [50] found that reactive oxygen species (including superoxide anion, hydroxyl radical, hydrogen peroxide, and peroxyl radical) and reactive nitrogen (including nitric oxide and peroxynitrites) levels of RA patients were significantly higher than those in the control group. In turn, the body has an antioxidant defense mechanism to neutralize free radicals and ROS. However, these antioxidant defense mechanisms can be compromised in RA patients, leading to intensified oxidative stress. Catalase, a crucial element of the human antioxidant defense mechanism that protects cells against ROS damage, was reported to be reduced in erythrocytes from RA patients [51]. Furthermore, decreased levels of glutathione defense systems, including glutathione and glutathione peroxidase, are closely associated with RA [52]. Secondly, there exists a remarkable association between oxidative stress and inflammation. The accumulation of free radicals, ROS, and reactive nitrogen species can activate and regulate a series of inflammation signal transduction pathways, in particular the nuclear factor kappa-B (NF-κB) [53, 54] and mitogen activated protein kinase (MAPK) [55] signaling pathways. For example, on the one hand, ROS can induce the activation of NLRP3 inflammasome, which interacts with NF-κB signal [56], and on the other hand, it mediates the activation of MAPK pathway [57], thereby promoting the generation and secretion of inflammatory cytokines and mediators, exacerbating the inflammatory response and joint damage of RA. Thirdly, excessive oxidative stress may not only activate cell death signals, triggering chondrocyte injury, further aggravating joint tissue destruction [58], but also affect cell functions by changing cell signal transduction pathways, including cell proliferation, differentiation, and migration [59]. All these may affect the progress of RA. Fourthly, studies have shown that strong antioxidants such as vitamin C and vitamin E may help reduce oxidative stress and thus combat the symptoms of RA [60]. These antioxidants neutralize free radicals and reduce the inflammatory response, probably benefiting from alleviating symptoms of RA.

In conclusion, OBS serves as a robust indicator of the body’s oxidative stress level. Our study revealed that TOBS, as well as DOBS and LOBS, all negatively correlated with RA in women. Moreover, it is meaningful to develop prevention measures for RA based on OBS. Advocating antioxidant dietary patterns and an antioxidant healthy lifestyle can enhance OBS and may protect the female population from RA. In contrast, pro-oxidant factors such as excessive fat intake, obesity, and smoking reduce OBS, which may accelerate RA development. More studies on OBS and RA in the future will assist in better illuminating their correlation.