Association between rheumatoid factor and metabolic syndrome in general population

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by excess morbidity and mortality from cardiovascular diseases (CVD). Moreover, the increased CVD risk seems like to be evident even in the subclinical stage [1‐3]. Metabolic syndrome (MS) is defined as a set of manifestations that are contemplated as cardiovascular risk factors (obesity, hyperglycemia, dyslipidemia, and hypertension), that along with systemic chronic inflammation, contributes to CVD development. The prevalence of MS in RA has been widely investigated, and a higher prevalence of MS has been noted among RA patients [4, 5].

Rheumatoid factor (RF) is most commonly used as a part of the diagnostic criteria for RA. Besides, RF is also found in patients with other inflammatory conditions and is present in 1–5% of healthy subjects. In RA patients, both increased risk of CVD and prevalence of MS have been reported to be associated with the elevation of auto-antibodies and inflammatory markers, including RF [5‐8].

In general population, RF has also been reported in few studies to be associated with cardiovascular morbidity and mortality [9‐11]. However, the present results are still controversial. Until now, the association of RF and MS has never been discussed in general population. Thus, this study aims to investigate the relationship between RF and MS, explore the potential value of RF for assessment of metabolic status, and further provide a reference to establishment of CVD primary prevention for this population.

It is unknown whether elevated levels of RF in the general population are associated with increased prevalence of MS. Herein, we demonstrate that the higher RF is associated with a greater MS prevalence in 13,690 Chinese who participated in a health-screening examination. The ORs for MS increase with the RF levels (about 1.42 according to the revised NCEP ATP III and 2.36 according to the IDF criteria, in the highest RF quartile compared to the lowest RF quartile).

The underlying causal mechanism of the association between RF and MS remains unclear. The possible functions of RF include the activation of the chronic inflammatory pathway. In fact, many conditions involving in chronic inflammation are associated with RF elevation [15]. In our study, ORs for MS, especially according to the IDF criteria, in higher RF quartiles markedly decreased after hsCRP level had been adjusted for. Thus, it is likely that elevated RF indicates low-grade chronic inflammation caused by immune complexes, which plays an important part. Nevertheless, we still notice that the association between RF and MS were significant after adjusting for hsCRP. This suggests that other biological pathways independent of inflammation are involved in, such as altered humoral immunity. In fact, mechanism of the association between RF and MS might be more complex, because adiposity in MS subjects wound simultaneously trigger the release of adipokines or other mediators and influence the production of auto-immune antibodies [3, 4].

As we known, none has discussed the association between RF and MS in general population this before. Few studies have addressed the association between RF and CVD morbidity and mortality in the general population. In the study by Tomasson et al. [10], RF was associated with greater all-cause and cardiovascular mortality in the general population, although the study included subjects with inflammatory arthritis. Edwards et al. [16] had reported that higher RF level was an independent risk factor for coronary artery disease (CAD) in men from the general population. Nevertheless, Nossent et al. [11] had reported that RF detected by Latex agglutination did not independently predict CVD or death in the general population in the Busselton Health Survey.

Data on the association between RF and the metabolic components are mostly from the secondary or baseline analysis of cohort studies, and are still conflicting. In the study by Tomasson et al. [10], as discussed above, RF-positive subjects had greater diabetes prevalence and lower cholesterol levels than RF-negative subjects in a general population cohort. In the cohort study to determine whether RF was associated with mortality from all-cause, CVD and cancer in Korean healthy adults, obesity and TG and HDL-C levels were not significantly different between RF-positive and RF-negative subjects at baseline [9]. Jafarzadeh et al. [17] conducted the cross-sectional study aiming to evaluate the serum levels of several autoantibodies in patients with ischemic heart disease (IHD) compared to healthy population and found no difference in RF levels in IHD patients with traditional risk factors, including hypertension, dyslipidemia, diabetes, and those without a certain risk factor. In the present analysis, overweight/obesity was most strongly associated with RF, which, along with insulin resistance, has been widely considered as the key point of MS. This suggests the important role of overweight/obesity in connecting the elevated RF with the greater MS prevalence, and also explain the stronger association between RF and MS by the IDF, which takes obesity as a essential component, than MS by the revised NCEP ATP III. Surprisingly, low HDL-C and hypertriglyceridaemia were negatively correlated with RF here. It had been reported that, HDL-C levels were persistently low but, along with its atheroprotective roles, fluctuate as a consequence of alterations in disease activity in RA. TG levels in RA were still controversial. Small study sample size and differences in the populations had been explained for this controversy [18, 19]. But here, mechanism of the association between relatively higher RF and higher HDL-C and lower TG in general population needs being further explored. In addition, no significant association of hyperglycaemia (after adjusting for covariates)were obtained. There might be more influential factors for blood glucose.

To our knowledge, this is the first study exploring the association between RF and MS in Chinese general population, who have a relatively healthy status. And the results are persuasive with the large study sample size and the sufficient statistical power. However, our study has several limitations. Firstly, we could not completely exclude all patients with RA as well as other diseases likely to influence the results by the way of self-statement. Moreover, individual history of smoking and drinking were not collected. Thus, this might result in some degree of residual confounding. Secondly, we use BMI instead of WC to define MS according to CDS criteria. This might not accurately reflect the level of visceral fat as well as the status of metabolism. Thirdly, this is an retrospective cross-sectional analysis, which could not declare the casual function of RF on the incidence of MS and its influence on CVD risk. In the further, prospective and mechanism studies need to be carried out.

RF level is associated with MS prevalence in general population. RF might be a valuable biomarker for assessment of metabolic status in this population. On the other hand, we should explain the meaning of RF in those with MS carefully. This study helps to provide a reference to the establishment of CVD primary prevention for this population.