1. IntroductionRheumatoid arthritis (RA) is a common chronic inflammatory condition that primarily affects the joints [1]. In Europe and North America, its prevalence ranges from 0.5% to 1.0%, with some Native American populations showing high prevalence [2]. Recent evidence suggests that RA contributes significantly to the growing health care costs in the United States [3]. While the exact mechanism by which RA develops and progresses is unknown, inflammation has always been considered a key factor throughout the course of the disease [1]. Currently, the treatments available for RA, including nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and glucocorticoids, have diversified and prolonged survival. However, despite the remarkable progress in therapeutics, partial or non-responders have still been observed, and the incidence of chronic co-morbidities, including metabolic syndrome (MetS) and cardiovascular disease, has been increasing over time [1,4]. Therefore, the recent recommendations of the European League Against Rheumatism (EULAR) for the management of these significant medical challenges include lifestyle interventions via a multidimensional approach [5].RA has been associated with a higher incidence of MetS and insulin resistance due to the hyperinflammatory state, which poses a challenge for treatment. MetS refers to a cluster of factors, such as central obesity, hypertension, high triglycerides, and low high-density lipoprotein cholesterol levels (HDL-C). The underlying pathophysiology of MetS is thought to be associated with insulin resistance [6]. Evidence in patients with RA has shown that the disease state and MetS influence each other. On the one hand, inflammation associated with RA itself and the drugs used to treat it, including glucocorticoids, can lead to metabolic abnormalities. On the other hand, the abnormal control of glucometabolic and lipid metabolism promotes the development of inflammation. The complex interactions between inflammation, treatment, and metabolism increase the prevalence and severity of MetS in patients with RA to some extent. However, the presence of MetS can still partly limit the treatment of RA. Therefore, nutritional intake has gained widespread attention from patients and physicians [7]. Estimates have shown that 500 billion cups of coffee are consumed annually around the world, making it one of the most popular beverages worldwide [8]. Caffeine may reduce the risk of developing type 2 diabetes mellitus (T2DM), one of the key components of MetS [8]. However, current research remains controversial regarding the effects of coffee consumption on MetS due to different study designs and study populations. A case–control study including 250 people suggested two to three cups of coffee a day was inversely associated with the incidence of MetS [9]. Another cross-section survey from the HAPIEE study that included 8821 adults showed that coffee was associated with reduced risk of MetS [10]. However, a population-based prospective cohort study by Lutsey et al. that included 9514 middle-aged adults (45 to 64 years old) and examined the relationship between their dietary data and MetS ultimately found no relationship between the incidence of MetS and coffee consumption [11]. Similarly, an epidemiological study based on a Chinese cohort did not suggest a significant association between MetS and coffee intake [12]. Moreover, no evidence has shown an association between coffee consumption and a lower likelihood of developing MetS among RA patients in the complex context of inflammation and metabolism.

The current study examined the association between coffee consumption and MetS severity among 1094 participants in the National Health and Nutrition Examination Survey (NHANES) 2003–2018 database. To the best of our knowledge, this has been the first study to focus on coffee consumption and MetS in patients with RA.

4. Discussion

Coffee has been associated with metabolism outcomes among individuals with, or at risk for, MetS. These associations, however, remain controversial due to different study designs and study populations. Moreover, few studies have focused on the relationship between MetS and coffee in patients with RA. The current study therefore clarifies several aspects of coffee’s relationship to MetS status in patients with RA based on the NHANES 2003–2018 database. First, we found that coffee consumption was associated with the severity of MetS in patients with RA. Second, given that our data comes from a 16-year nationwide population survey, it is nationally representative and uniquely free of selection bias. Third, two 24-h dietary recalls (the gold standard for nutritional epidemiology) and MetS z-score (a widely used tool to evaluate MetS) were used to quantify coffee consumption and the severity of MetS, respectively. Finally, to address potential confounders, we introduced decaffeinated coffee and total caffeine intake as control groups and performed sensitivity analyses.

The findings of the current study showed that BMI was lower among those who consumed >2 cups of coffee per day, although no significant difference in total daily energy intake was observed. In fact, coffee has been shown to be beneficial for weight loss for over a decade [22]. This may be related to the biological function of caffeine. Caffeine is one of the important components of coffee, which belongs to a group of compounds called methylxanthines. The thermogenic effects of caffeine had been observed a few years ago. Although the mechanism has yet to be fully clarified, it is mainly thought to be due to the inhibitory effects of the phosphodiesterase-induced degradation of intracellular cyclic AMP (cAMP) and antagonism of adenosine receptors [23]. Kevin et al. also revealed the lipolytic effects of caffeine mediated via the sympathetic nervous system [24], although our study suggested no effects on lipid levels in patients with RA. Furthermore, caffeine increases energy expenditure while decreasing energy intake, thereby affecting the energy balance [22]. Thus, caffeine had been proposed as a strategy for weight loss and weight maintenance given its effects on thermogenesis, fat oxidation, and negative energy balance [22,25]. The above mechanism explains the association of coffee intake with lower BMI in our study. Interestingly, no significant correlation was observed between daily total caffeine intake and severity of MetS in our study. This may be attributed to two aspects. On the one hand, considering decaffeinated coffee consumption was also not associated with z-score, the effect of coffee on metabolic syndrome severity may be a combination of caffeine and other components such as phenolic compounds. On the other hand, we found that caffeine consumption was positively correlated, and this may due to the fact that other caffeine-rich foods, such as sweetened beverages, hot cocoa, and chocolate, are often associated with high fat and sugar, which may increase the risk of metabolic syndrome.The present study found a negative correlation between coffee intake and blood pressure. Although caffeine intake causes a sharp increase in blood pressure, habitual coffee drinkers did not exhibit greater blood pressure with elevated levels of caffeine in the blood compared to non-habitual drinkers, which may due to other substances in coffee [26]. A large prospective cohort study that included 8780 participants without hypertension suggested an inverse relationship between moderate coffee intake (1–3 cups/day) and the risk of developing hypertension [27]. In addition, a dose–response meta-analysis of prospective cohort studies, which focused on the risk of relationship between increased coffee consumption and the risk of hypertension, also showed an inverse association [28]. The phenolic compounds contained in coffee have been widely believed to improve blood pressure [29]. Among them, chlorogenic acid and caffeic acid were proven to exert antihypertensive effects via their antioxidant properties [30]. Apart from the traditional risk factors for hypertension, other factors in RA may affect blood pressure and its control, such as inflammation, medications, and physical inactivity [31]. Elevated C-reaction protein (CRP), which reflects systemic inflammation, was found to reduce endothelial nitric oxide production, leading to vasoconstriction [32]. Additionally, CRP can upregulate angiotensin type-1 receptor expression, affect the renin–angiotensin system, and contribute to high blood pressure [33]. However, a metabolite of chlorogenic acid, ferulic acid, has been shown to repair endothelial function by increasing the bioavailability of nitric oxide [34]. Moreover, proinflammatory cytokines expressed by vascular endothelial cells were reduced in response to coffee polyphenols [8]. In summary, coffee can affect the blood pressure of individuals with RA through several ways.However, the metabolic effects of coffee in RA are more complex. Unlike the normal population, the autoinflammation caused by immune dysfunction makes insulin resistance and MetS more prevalent and severe in RA, playing a key role in metabolic disorders [35]. A previous study by Dessein et al. found an association between insulin resistance and elevated markers of inflammation in RA [36]. Their study also showed a negative correlation between beta-cell function and disease activity. It can also be argued that the severity of insulin resistance and MetS reflect, to some extent, the state of immune disorders in rheumatoid patients. By reducing proinflammatory cytokines, macrophage and natural killer cell activity, and B and T cell proliferation, caffeine affects the immune system [37]. It is this immunomodulatory function that reduces the inflammation-related resistance in patients with RA. Therefore, our study showed the immunomodulatory effects of caffeine in the high-risk group might gradually negate its effects on insulin resistance and sensitivity with increasing intake (i.e., more than two cups of coffee per day), thereby reducing the risk of MetS while leaving blood glucose unaffected. In the low-risk group, who may have less inflammatory involvement, 2 cups of coffee per day; hence, these participants showed no decrease in z-scores and had higher glucose levels.Dyslipidemia is also an important component of MetS. The effects of coffee on patients with RA are complex. On the one hand, the inflammation and treatment of RA itself can lead to changes in blood lipid levels. Several studies have shown a decrease in total, LDL and HDL cholesterol and triglycerides in RA with high-grade inflammation; however, no such decrease was observed in stable disease, non-inflammatory arthritis, or normal controls [38,39]. This could be attributed to inflammation-activated oxidation or scavenger receptor pathways, leading to a negative balance in cholesterol synthesis, or to the production of autoantibodies against LDL [40]. Regarding therapeutic drugs, hydroxychloroquine has been proven beneficial for lipid profiles; however, glucocorticoid use contributes to dyslipidemia [41]. Nonetheless, most investigators agree that coffee intake is associated with an increased risk for dyslipidemia [42]. The pooled results of a recent meta-analysis that included 12 RCT demonstrated a significant positive association between coffee and total cholesterol, triglycerides, and LDL cholesterol [42]. Evidence has shown that either the lipid compounds contained in coffee or individual genetic variation may be responsible for the reduced synthesis and release of bile acids [42]. However, chlorogenic acid, the main phenolic compound in coffee, has been found to have anti-lipid properties [43]. Therefore, the mechanism by which coffee exerts its lipid metabolizing effects remains unclear. The current study found that coffee, decaffeinated coffee, and caffeine intake had no effect on lipid profiles in patients with RA, which may suggest that coffee and inflammation act together and then achieve a balance. More research is needed to determine the mechanism by which coffee affects lipids in patients with RA.Interestingly, when patients were divided into groups with and without metabolic syndrome, we found no significant association between coffee and the development of metabolic syndrome. Actually, lots of studied have focused on the relationship between coffee and prevalence of MetS, whereas the results are controversial [9,10,11,12]. This may be due to selection bias, study design, and differences sample size. In our study, for example, the difference in the sample size between the two groups (with or without MetS) was significant, which may cause statistical errors. In addition, there are differences in the five widely used classification criteria for MetS, which could also lead to selection bias. Therefore, we mainly used the MetS z-score with higher sensitivity in this study to help us define whether patients have metabolic disorders, which is also meaningful in practical clinical applications to achieve early diagnosis and intervention. In fact, our findings do suggest that the z-score can identify more people at risk for metabolic disorders (730 for z-score vs. 169 for NCEP/ATPIII). However, follow-up studies are needed to compare the efficacy of the z-score and the classification criteria.

The present study has several strengths. Primarily, the data for our study came from the NHANES, thereby ensuring high quality. Moreover, we included a wide range of potential confounders closely associated with RA and MetS to provide more reliable results. Moreover, we used decaffeinated coffee and caffeine intake as control groups and conducted sensitivity analyses to increase the plausibility of our results.

Nonetheless, our study has several limitations worth noting. First, this was a cross-section study, which limits causal inferences. In addition, we lacked data on inflammatory markers, which are important for patients with RA, although these autoinflammatory conditions ultimately affect MetS by influencing its components. Moreover, due to missing data, we could not categorize coffee according to bean type, roasting, and brewing method. Last, although our application of the MetS z-score to determine a patient’s risk of MetS may not be the most comprehensive, and some studies have shown this scoring system to be reliable [15,16].