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The relationship between animal flesh foods consumption and rheumatoid arthritis: a case-control study

Background Rheumatoid arthritis (RA) is a chronic, systemic inflammatory, and debilitating autoimmune illness. The objective of the present study was to evaluate the relationship between animal flesh foods consumption and rheumatoid arthritis. Methods Meat consumption was assessed by using a semi-quantitative Food Frequency Questionnaire (168 items) in a case-control study of 297 subjects (100 newly diagnosed cases and 197 healthy controls). An expert rheumatologist diagnosed patients based on the American College of Rheumatology definitions, 2010. Multivariate logistic regression, adjusted for lifestyle and nutritional confounders, was used to evaluate the relationship between dairy consumption and rheumatoid arthritis. Results Participants with greater consumption of fish and seafood were less likely to have RA (OR 0.52; 95% CI 0.27–0.98). Conversely, a higher processed meat intake was associated with increased odds of RA (OR 3.45; 95% CI 1.78–6.68). However, no significant association was found between red meats and poultry consumption and the risk of RA in the fully adjusted model. Conclusions The present study suggests an inverse association between fish and seafood consumption and the risk of RA. On the contrary, a higher amount of processed meat intake was associated with increased odds of RA. However, further studies are warranted to confirm the veracity of our findings.


Background
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory, and debilitating autoimmune illness that is more common in women and affects about 1% of the world's population [1,2]. The main characteristics of RA include chronic inflammation of the synovial tissue, progressive destruction of cartilage, bone erosion, pain, and eventually, permanent joint damage [3,4]. The disease can have extensive negative effects on quality of life and life expectancy, increases healthcare use, contribute to a loss of work, and represents a substantial economic burden, both individually and societally [5,6]. Although the cause of RA is not yet fully understood, according to various reports, genetic and environmental factors are implicated in the expression of the disease [7]. Environmental risk factors that can play a role in the progression and/ or development of RA include smoking, socioeconomic, stress, viruses, and diet [8,9]. Diet represents a modifiable risk factor that can act as a disease trigger or an inflammatory response moderator. Studies on diet and risk of RA may help to identify modifiable and preventative factors [10][11][12]. Several studies have shown correlations between dietary components and changes in inflammation and disease activity in patients with rheumatoid arthritis [13]; indeed, diets containing animal products (e.g., dairy and red meat) may exacerbate RA due to their pro-inflammatory properties [14]. The prevalence of autoimmune diseases is higher in Western countries, which can, at least partly, be attributed to, or influenced by, dietary habits [15]. In fact, the Western diet, which is typically high in saturated and trans fats, refined carbohydrates, sugar-sweetened drinks, and a low ratio of omega-3: omega-6 fatty acids, increases inflammation and the risk of RA. The main feature of the Western diet is the high consumption of animal proteins and red meat, which, in a nested case-control study, was reported to increase the risk of inflammatory polyarthritis [16,17]. However, another case-control study in China, which was conducted on 968 patients with RA diagnosed according to American College of Rheumatology criteria and 1037 matched healthy controls, found no association between red meat intake and the risk of RA [18]. Although a number of studies have shown a reduced risk of RA with increased fish consumption [19], there are numerous contradictory findings that require further study [18,20]. Indeed, due to the controversies between studies and the lack of evidence in Iran, the present study was conducted to investigate the relationship between animal flesh foods consumption and RA.

Study population
Details on the methodology of the present study have been previously reported [21]. Briefly, in this case-control study, newly diagnosed RA patients (maximum 12 months since diagnosis) who attended a rheumatology clinic in Isfahan, Iran, were recruited. The presence of RA was confirmed by a rheumatologist based on the American College of Rheumatology 2010 classification criteria [22]. Eligibility criteria included: lack of a history of chronic diseases, such as cardiovascular diseases, renal disease, liver diseases, or cancer; not pregnant or lactating; not consuming alcohol; have no known food allergies or adhering to special lifestyle/diets. Furthermore, we excluded participants who did not complete the Food Frequency Questionnaire (FFQ), did not answer more than 35 items of the questionnaire, or whose energy intake showed extremely high or low (energy intake 800-4200 kcal/day) [23]. All participants gave written informed consent. This study was approved by the Research Council and the Ethics Committee of Isfahan University of Medical Sciences (IR. MUI.Research. REC.1398.120).

Dietary assessment
Diet was assessed using data from a semi-quantitative Food Frequency Questionnaire (FFQ) containing the frequency and the amount of dietary intake. The FFQ was validated previously in Iranian populations [24]. The questionnaire included 168 food items, and information was collected through interviews by a trained dietitian. The frequency of meat consumption (red meat, poultry, fresh fish, canned fish, processed meats, and organ meats) was assessed with a questionnaire response regarding the average consumption of various foods over the past year, ranging from never to three times or more per day.

Assessment of other variables
Anthropometric data were assessed through standard methods. Body weight was measured by a digital scale, to an accuracy of 100 g, with participants unshod and in light clothes. Height was measured using a non-stretchable measuring tape, with participants in a standing position and unshod. Body mass index (BMI) was calculated through the following formula: weight in Kg divided by height in m squared. Also, waist circumference was obtained from the midpoint region between the undersides of the rib and the upper part of the pelvis using a non-stretch plastic measuring tape.
Data regarding demographic features and socioeconomic status (SES) of the participants were collected through a self-reported questionnaire. Variables included: age, sex, education (below high school diploma; diploma; diploma to bachelor's degree; on top of bachelor's degree), type of occupation, home status (owner/ tenant), home type (apartment/villa), family size (≤4/> 4), family the disease history as well as smoking status.
Physical activity rate was assessed by the use of a validated and reliable short form of the International Physical Activity Questionnaire (Short IPAQ) [25]. Participants responded to seven questions regarding low, intermediate, and high levels of physical activity. Then physical activity rate of each subject was measured by metabolic equivalent task (MET) -minutes/day.

Statistical analyses
All analyses were conducted using SPSS (version 21.0, SPSS Inc., Chicago, Illinois, USA). The normal distribution of data was examined by the Kolmogorov-Smirnov test. To explore the difference in general characteristics, macronutrients, and animal meat intake between case and controls, independent t-test or Chi-square were applied based on the nature of the data. Multi-variable adjusted models were used to investigate the association between different types of animal meat consumption and risk of RA in three different models; crude model with no adjustment; model 1, which was controlled for age, sex, BMI, and physical activity; and model 2 with additional adjustment for total energy intake, smoking, socioeconomic status (SES), drug use and family the disease history. A P-Value of less than 0.05 was considered, a priori, to represent statistical significance.

Result
At the recruitment of study participants, 100 cases and 197 sex-matched controls were eligible based on the inclusion/exclusion criteria. Table 1 presents the general characteristics of study participants for each group. The mean age of cases and controls were 49.26 ± 12.6 and 40.88 ± 9.72y, respectively (P-value: < 0.001). There was no significant difference in the proportion of men/ women between the case and control groups. The remaining variables, including BMI, family history of the disease, drug use percentage, smoking levels, total energy, protein and fat intake, and physical activity levels, were significantly higher in the case group than control, whilst a higher socioeconomic status, education, and carbohydrate intake were seen in the control compared to the case group.
The mean and SD of different types of meat consumption, in both cases and controls, are shown in Table 2. There was a significant difference between cases and controls in terms of consuming processed meat, fish, and seafood; however, the amount of red meat, organ meat, and poultry intake was approximately the same in the case and control groups.
Multi-variable adjusted OR for the risk of RA across the median of meat intake are shown in Table 3 and Fig. 1. Compared to those in the lower median, those in the upper median of processed meats consumption had  Finally, no significant association was found between red meats and poultry and the risk of RA.

Discussion
The present case-control study assessed the relationship between animal flesh food consumption and the risk of RA. The results of this study indicate an inverse association between fish consumption and RA. In addition, we noted a significant direct association between processed meat intake and an increased risk of RA, whilst the other variables in meat groups, including intake of red meat, poultry, and organ meat, did not show any significant association with the disease. RA is a debilitating disease that adversely affects patients' abilities to perform normal daily activities and incurs high economic and societal costs due to the  [5,6,26].
In the present study, we showed that participants with higher consumption of fish were less likely to have RA. Concordant with our results, the association between fish consumption and a reduced risk of RA has been shown in many empirical studies [27,28]. Indeed, evidence suggests that consumption of individual foods, including fish, might reduce the risk of RA. In a case-control study conducted by Rusell et al. [29] on 1889 patients and 2146 controls, the results showed that consumption of oily fish reduced the risk of RA while intake of fish oil supplements did not show a beneficial result. In another study of 32,000 women in 1987 and 1997 from the Swedish Mammography prospective Cohort, Giuseppe et al. [30] found that intake of 1-3 servings of fish per week reduced the risk of RA. However, the results of a casecontrol study conducted in China failed to find a significant association between fish consumption and the risk of RA [18]. The reason for underlining this discrepancy is unclear. It might be due to differences in dietary habits and the usual amount of intake, which is specific for people from various regions. For instance, the amount of seafood intake reported in this study is much higher compared to our study. The association between fish intake and the risk of RA found in the present study might be attributed to the anti-inflammatory properties of fish oil [31,32]; however, this is a complex interaction, and other fatty acids could also exhibit pro-or anti-inflammatory activity [33,34].
Our study showed that greater consumption of processed meat was related to an increased risk of RA. In this line, the EPIC-Norfolk study showed that individuals who ate higher levels of meat products (for instance, sausage) were more likely to develop polyarthritis [17]. Several studies have shown that processed meat can increase inflammatory mediators, including CRP [35][36][37]. Processed meat refers to products that are usually made from red meat and cured, salted, or smoked to improve the taste, color, and shelf life. Processed meats, such as sausages, have a high amount of fat (Often 50% by weight of sausage or more), SFA, and cholesterol [38]. In general, processed foods maybe increase the intake of saturated fats, cholesterol, salt, nitrite, heme iron, and polycyclic aromatic hydrocarbons, depending on methods used for food preparation [39]. Thus, the result might be due to these various components, knowing that they play an important role in oxidative stress [40].
In the present study, we failed to find any significant association between red meat and poultry consumption and the risk of RA. Similar to our findings, the results of a cohort study in the United States showed no association between red meat and poultry and the incidence of RA [33]. Another prospective cohort (Nurses' Health Study) conducted on 82,063 women, which followed participants for more than 20 years, could not find a significant association between red meat intake and RA incidence [41]. Although some empirical studies indicated that greater red meat consumption is correlated with an increased risk of RA [42,43] and put the finger on Arachidonic acid as one of the components of red meat that can trigger the production of inflammatory agents [44], recent investigations revealed a different role for this fatty acid [45][46][47]. In addition, meat also contains iron, which is known as a risk factor for oxidative stress; however, studies have shown that the increased risk of RA with meat consumption is independent of iron intake, and no association was found between iron consumption and RA [17]. Perhaps the difference in study results can be attributed to methodology differences, age groups, study populations, diet, and other lifestyle factors. Indeed, such reports in the literature may help to explain why our study did not detect an association between red meat and RA. In addition, since we did not measure the blood concentrations of the various components in participants, we could not say with certainty whether the effect of micronutrients and their role in RA.
The major strengths of this study are the recruitment of newly diagnosed patients, which reduces the likelihood of dietary changes since diagnosis. We controlled the effects of several potential confounders in the statistical analyses, which aided in our ability to provide more accurate interpretations of the data. Notwithstanding these strengths, our study had a number of limitations that should be considered, including we recruited a relatively small sample size and evaluated dietary intake by using a self-reported 1-year FFQ, which may increase the possibility of error in measuring dietary intake as it mainly depends on the memory of participants. Furthermore, the participants of this study were only from Isfahan, Iran; thus, we cannot necessarily extend these results to all Iranians or indeed different countries or ethnicities. Moreover, the participants' age, which has been suggested to be a risk factor for RA, was significantly different between the case and control groups; however, we controlled and minimized the effect of this confounder on the findings through the multivariable adjustment models. Finally, it should be mentioned that our results may have been influenced by some potential confounders that were not evaluated, such as genetic factors and stress levels. Thus, considering the strengths and limitations of our study, we strongly recommend that large-scale investigations into the association between dietary factors, particularly red meat and fish, be conducted, including diverse ethnic samples.

Conclusion
The present study suggests that a higher fish and seafood intake might be associated with a decreased risk of RA, while a greater amount of processed meat consumption may be associated with an increased odd of the disease. It is well known that patients who suffer from RA encounter numerous restrictions and difficulties; our results provide better insight into the association between RA and different types of meat foods and further highlight the importance of dietary assessment in this patient group. Nevertheless, further studies with higher sample sizes and more diverse ethnicities and geographical locations are recommended to confirm the veracity of these findings.