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26 September 2020

Environment and Lifestyle: Their Influence on the Risk of RA

,
,
and
1
Centre for Research in Epidemiology and Population Health, (CESP), INSERM U1018, Université Paris-Sud, F-94800 Villejuif, France
2
Rheumatology Department, Centre Hospitalier Régional d’Orléans, 45100 Orléans, France
3
Centre of Immunology of Viral Infections and Auto-immune Diseases (IMVA), INSERM U1184, Université Paris-Sud, F-94270 Le Kremlin Bicêtre, France
4
Department of Internal Medicine, AP-HP. Nord, Hôpital Beaujon, Université de Paris, F-92100 Clichy, France
J. Clin. Med.2020, 9(10), 3109;https://doi.org/10.3390/jcm9103109
This article belongs to the Special Issue Rheumatoid Arthritis: Pathogenesis, Diagnosis and Therapies
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Abstract

Background: Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that lead to triggering of autoimmunity. Methods: We reviewed environmental, hormonal, and dietary factors that have been suggested to be associated with the risk of RA. Results: Smoking is the most robust factor associated with the risk of RA, with a clear gene–environment interaction. Among other inhalants, silica may increase the risk of RA in men. There is less evidence for pesticides, pollution, and other occupational inhalants. Regarding female hormonal exposures, there is some epidemiological evidence, although not consistent in the literature, to suggest a link between hormonal factors and the risk of RA. Regarding dietary factors, available evidence is conflicting. A high consumption of coffee seems to be associated with an increased risk of RA, whereas a moderate consumption of alcohol is inversely associated with the risk of RA, and there is less evidence regarding other food groups. Dietary pattern analyses (Mediterranean diet, the inflammatory potential of the diet, or diet quality) suggested a potential benefit of dietary modifications for individuals at high risk of RA. Conclusion: To date, smoking and silica exposure have been reproducibly demonstrated to trigger the emergence of RA. However, many other environmental factors have been studied, mostly with a case-control design. Results were conflicting and studies rarely considered potential gene–environment interactions. There is a need for large scale prospective studies and studies in predisposed individuals to better understand and prevent the disease and its course.

1. Introduction

The immune onset of rheumatoid arthritis (RA), so called “preclinical phase” of the disease, might occur several years before the first symptoms of RA, with the development of autoimmunity as evidenced by detectable anti-citrullinated peptide antibodies (ACPA) and rheumatoid factors (RF). The “mucosal paradigm” hypothesizes that environmental factors may lead to inflammation of the pulmonary or the gut mucosa, and to locally prime autoimmunity in individuals with genetic predisposal, leading to autoantibody production years before RA onset [1].
The involvement of environmental, dietary, reproductive, and lifestyle factors in the pathogenesis of RA is supported by numerous observations which include the following: two thirds of individuals who develop RA are women, suggesting the role of female hormones; also the latitude gradient influences the incidence of RA and age at onset, and the socioeconomic status and educational levels are consistently associated with the risk of RA [2,3,4,5].
The aim of this study is to review the literature evidence on external and internal exposures (so called “exposome”) associated with the risk of RA and its phenotype, and their interaction with genetic risk factors. First, we discuss cigarette smoking, which is the main environmental risk factor for RA, then, we discuss other inhalants, female hormonal and reproductive factors, and dietary factors.

2. Cigarette Smoking

2.1. Active Cigarette Smoking

Smoking is the most robust and well documented environmental risk factor associated with RA. A meta-analysis by Di Giuseppe et al. included three prospective cohorts and seven case-control studies [6,7,8,9,10,11,12,13,14,15,16]. A comparison with never smokers showed that those who had 1 to 10 pack-years of smoking had a 26% increased risk of RA (relative risk (RR) = 1.26, 95% CI 1.14–1.39), whereas risk doubled among those with more than 20 pack-years (RR for 21–30 pack years = 1.94, 95% CI 1.65–2.27, and RR for >40 pack-years = 2.07, 95% CI 1.15–3.73). In addition, the risk associated with the highest versus the lowest category of pack-years of smoking was higher for RF-positive RA (RR = 2.47 and 95% CI 2.02–3.02) than for RF-negative RA (RR = 1.58, 95% CI 1.15–2.18).
The risk of RA associated with smoking was generally higher among men than among women [17]. Interestingly, the association between smoking and RA decreased after smoking cessation. Twenty years after smoking cessation, there was no longer any association between smoking and ACPA-negative RA, whereas the association with ACPA-positive RA risk persisted and remained linked to the cumulative dose of cigarette smoking [17,18,19].

2.2. Interaction between Smoking and Genetic Risk Factors for Rheumatoid Arthritis (RA)

Numerous studies have investigated the interaction between a well-known genetic risk factor (HLA-DRB1 shared epitope (SE)) and smoking on RA development for both antibody positive and antibody negative RA [19,20,21,22,23,24,25]. Smokers carrying two copies of the SE were at a 21-fold increased risk of ACPA-positive RA as compared with non-smokers carrying no SE copy [25]. Moreover, SE- and smoking-related risk of ACPA-positive RA increased with the intensity of smoking and the number of SE alleles (Figure 1) [19]. These results suggest a strong gene–environment interaction with a dose-response effect for both genetic and environmental factors for the risk of ACPA-positive RA.
Figure 1. Odds ratios (OR) for ACPA-positive rheumatoid arthritis (RA) and different amounts of smoking (pack-years) in combination with none (no shared epitope (SE)), one (single SE), or two (double SE) copies of SE alleles. The reference group being no smokers without SE alleles. Figures from Källberg et al. Smoking is a major preventable risk factor for rheumatoid arthritis. Estimations of risks after various exposures to cigarette smoke. (Ann. Rheum. Dis. 2011; 70:508-11 [19].)
To date, the main pathogenetic hypothesis for this interaction concerns the presence of citrulline-modified proteins in the lungs of smokers (due to local mucosal inflammation) leading to a systemic immune response to these citrullinated proteins by ACPA production, preferentially induced in individuals carrying SE genes (having higher affinity for citrullinated peptides) [25,26,27,28].
Multiple other genetic factors have also been associated with RA such as PTPN22, PADI4, CTLA-4, STAT4, etc. [29]. For PTPN22, the risk was stronger for RF positive than for RF negative RA [30,31]. PTPN22 and PADI-4 polymorphisms may also lead to hypercitrullination and may be implicated in ACPA production and the development of RA. Nevertheless, interactions between those genetic risk factors and smoking, and according to RA subsets, remain unclear [32,33,34,35,36].

2.3. Passive Smoking, Including Fetal Exposure through Maternal Smoking

Few studies have examined risks associated with passive smoking. In adulthood, passive smoking exposure at work or at home was not associated with RA in three case-control and cohort studies [7,37,38]. In a cohort of French women from the education system, ever-smokers with passive smoking exposure during childhood had a higher risk of RA than smokers with no passive smoking during childhood [39]. In another study, high maternal smoking during pregnancy (>10 cigarettes per day) increased the risk of RA and other inflammatory polyarthritis during childhood only in girls as compared with no maternal smoking (OR = 2.57, 95% CI 1.13–5.89) [40].
However, measurement of passive smoking is challenging and heterogeneous which might explain these discrepancies. Assessment of the effect of passive smoking on RA should also consider active smoking, timing, duration, and intensity of passive exposure.

3. Inhaled Exposures Other Than Smoking

Although tobacco consumption has decreased over the last decades, RA incidence remains stable in the USA [41]. Other inhalants may play a role since many non-smokers develop RA, by inducing pulmonary mucosal inflammation and systemic immune response with ACPA production [28]. This chapter summarizes available evidence regarding inhaled occupational exposures (silica, pesticides, and others), and air pollution (Table 1).
Table 1. Selected case-control and cohort studies on inhaled exposures associated with risk of rheumatoid arthritis.

3.1. Silica

Silica exposure is the second most documented environmental factor associated with the risk of RA. After adjustment for smoking, several cohort and case-control studies reported associations between RA in men and specific occupations such as granite workers, rock drilling, and stone crushing [42,45,48,49,50]. There was only one case-control study that reported an inverse association between silica exposure and RA risk among pottery, sandstone, and refractory material (aluminosilicate or silica) workers [43].
Similar to smoking, silica exposure has been mainly associated with seropositive RA [46,47]. In a Swedish register of silica-exposed male workers in iron foundries, individuals employed for at least one year had an increased risk of seropositive RA as compared with the general population (SIR=1.70, 95% CI 1.01–2.69) increasing to 2.59 (95% CI 0.24–4.76) among highly exposed individuals, with a dose-response relationship [71].
Interestingly, a high risk of ACPA-positive RA was observed among silica-exposed current smokers (OR = 7.36, 95% CI 3.31–16.38), suggesting an interaction between these exposures [46]. Few other studies supported such silica–smoking interaction [48,72]. These results must be taken with caution because smoking duration or intensity was not taken into account.
Thus, there is some evidence that occupational silica exposure in men could be a risk factor for seropositive RA with a dose-response relationship, and that smoking would increase the risk associated with silica exposure. This suggests that silica could share the same pulmonary mucosal inflammation pathway as smoking.

3.2. Pesticides

Two large Swedish studies reported no association between occupational pesticide exposures and risk of RA [44,62]. However, in a cross sectional study conducted among male pesticide sprayers in Greece, high pesticide exposure (total number of pesticide applications throughout the lifespan) was associated with RA (all pesticides OR = 43, 95% CI 3.09–600.67; for insecticide OR = 15.29, 95% CI 1.24–189.02; and fungicides OR = 14.3, 95% CI 1.38–150.37) as compared with low exposure [73].
The Agricultural Health Study (Table 1) provided information on ever-use of 50 pesticides with duration and frequency among farmers and spouses. Among male pesticide sprayers, fonofos, carbaryl, and chlorimuron ethyl were associated with increased RA risk, but not DDT or glyphosate. Dose-response associations with RA were observed for atrazine, toxaphene, and fonofos [54]. Among farmers’ spouses, the use of any specific pesticide among the 15 examined pesticides including glyphosate was slightly associated with RA as compared with no exposure (Table 1) [55,56].
In the Women’s Health Initiative Observational Study, residential or workplace insecticide use was associated with RA in post-menopausal women (p = 0.0026) [74]. Early-life pesticide exposure and farm residence during childhood increased the risk of adulthood onset of RA in women (Table 1) [57].
These conflicting results, regarding the effect of specific pesticide, may be explained by methodologies of the studies, exposure misclassification (mainly self-reported exposure), timing and frequency of pesticide use, and unmeasured confounding.

3.3. Others Inhalant-Related Occupations

Table 1 summarizes other inhaled occupational exposures potentially associated with RA risk. Some occupations would be associated with the risk of RA in men, such as construction workers (with studied exposures to non-silica dust, organic solvents, asbestos, vermiculite, or asphalt) and farmers (with studied exposures to chemical fertilizers, non-gasoline solvent, cleaning solvent, or farm animals) [44,48,56,58,59,60,62,63,64,75].
In men, coal dust has been associated with an elevated risk of RA and 33% of RA has been be attributable to coal mining work [50].
With less evidence, transportation workers (exposed to mineral oil), steel workers, plastic industry workers (exposed to styrene), military workers (exposed to smoke from open-air burn pits), and electronic workers (exposed to potential noxious airborne agents) may have an increased risk of RA (Table 1) [44,52,53,59,61,62,75].
In women, exposure to textile dust has been reported associated with an increased risk of RA with a potential interaction with SE [51].

3.4. Air Pollution

Air pollution is a mixture of gas pollutants including ozone (O3), carbone monoxide (CO), fine particulate matter (PM10, PM2.5), nitrogen dioxide (NO2), and sulphur dioxide (SO2).
Living close to a highway or a major road has been reported to be associated with a 30% increased risk of RA, suggesting a possible association with air pollution [65,66]. Intense dust and smoke exposures after the World Trade Centre’s terrorist attack have been associated with doubling the risk of systemic autoimmune diseases, mostly RA [76]. These results suggest a possible association between RA and air pollution.
However, high levels of exposure to NO2, PM2.5, PM10, and SO2 have not been associated with RA (Table 1), except for one study with no adjustment for smoking [66,68,69,70]. O3 and CO levels could be associated with RA [66,67].
However, results are still unclear, possibly due to discrepancies in measuring air pollution exposure (residential addresses prior or at diagnosis or traffic and home heating), and methodological limits regarding timing and accounting for confounders (such as smoking and the socioeconomic status).

4. Reproductive Factors in Women

The implication of female hormones in the pathogenesis of RA has been supported by numerous observations which include the following: a 2:4 female/male ratio before the age of 50 but below 2:4 after the age of 60, an increased incidence during postpartum, a peak of RA incidence around the age of menopause, and about 50% of RA starts during a woman’s reproductive life. During a woman’s life, some events such as pregnancy, postpartum, breastfeeding, menopause, and the use of exogenous hormones induce changes in female hormonal exposures. Indeed, estrogens and progestogens may have pro-inflammatory or anti-inflammatory effects depending on serum levels and reproductive stage (reproductive life, menopausal transition, and post-menopause). Then, during the menopausal period, the decline of estrogen and progestogen levels is associated with an increase of pro-inflammatory cytokines, such as IL-6, TNFα, and IL-1α [2]. Table 2 summarizes results from cohort and case-control studies, regarding reproductive factors and hormonal treatments.
Table 2. Selected case-control and cohort studies on reproductive factors and the risk for rheumatoid arthritis.

4.1. Ages at Menarche and Menopause

The role of early menarche on the risk of RA is unclear, with two cohorts and three case-control studies providing conflicting results [86]. Early age at menopause (≤44 or 45 years) was associated with increased risk of seronegative RA in two cohort studies and one case-control study [78,79,89]. Two other case-control studies did not find any association between age at menopause and RA risk [14,86].
Recently, Alpizar-Rodriguez et al. reported an increased incidence of ACPA-positive RA with menopause, especially in the early post-menopausal period (i.e., within <6 years after menopause) among women at risk of RA (first-degree relatives of patients with RA). This suggests that the acute decline in ovarian function could contribute to the development of autoimmunity and potentially to an increased risk of RA in women [93].

4.2. Parity and Postpartum

During the 12 or 24 month postpartum period, incident cases of RA are more frequent than later on [83,84,94]. The risk seems to be maximal during the first three months after delivery and reduces during the subsequent nine months [82]. This supports a role for hormonal changes during pregnancy or after delivery in RA onset. Because of the short time, it could be questioned whether RA arises de novo or rather RA symptoms arise in women with already triggered autoimmunity.
A high number of pregnancies could reduce the risk of RA [14,80,81,84,86] or could have no impact on the risk of RA [77,78,79,85] (Table 2). In line with those studies, a meta-analysis that included 12 studies demonstrated a borderline significant inverse association between parity (versus nulliparity) and RA (RR 0.90, 95% CI 0.79–1.02), and a significant nonlinear inverse relation between parity number and the risk of RA [95].
Contrarily, a case-control study showed that parous women (versus nulliparous) had an increased risk of seronegative RA in the age group 18–44 years, but not at older ages (45–70). The increased risk was attributable to an elevated risk during the postpartum period, and to a young age (≤22 years) at first birth as compared with nulliparity [83].

4.3. Breastfeeding

A meta-analysis including three case-control and three cohort studies suggested that breastfeeding was inversely associated with the risk of RA (OR = 0.67, 95% CI 0.5–0.9), whatever the duration [96]. Nevertheless, a dose response effect of duration of breastfeeding has been found in several studies (Table 2) [77,79,85], especially for ACPA-positive RA [83]. There were only two studies that did not find any association [14,78], and one case-control study that found an increased risk of RA associated with breastfeeding and its duration [86].

4.4. Benign Gynecological Diseases

Endometriosis is associated with high estrogen levels during a women’s reproductive period. A recent meta-analysis of five studies (two cross-sectional, one case-control, and two cohort studies) did not demonstrate any association between endometriosis and RA [97]. The pooled relative risk of the two prospective cohort studies was not statistically significant (RR = 1.46, 95% CI 0.70–3.03) [78,97,98]. Nevertheless, Harris et al. found a significant association between surgically confirmed endometriosis and RA (Table 2) [88].
Polycystic ovary syndrome, associated with anovulation and low serum progestogen levels, was associated with RA in a single cohort study (Table 2) [78].

4.5. Hormonal Treatments

Numerous studies have assessed the association between oral contraception (OC) and post-menopausal hormone therapy (PMHT) use with conflicting results, positive, negative, or null associations with risk of RA (Table 2).
A meta-analysis of 28 observational studies suggested a protective effect of oral contraception (OC) (ever versus never) in pooled case control studies (OR = 0.70, 95% CI 0.5–0.9) but not in pooled cohort studies (OR = 1.0, 95% CI 0.9–1.1). Current and past uses of OC were not associated with RA in pooled cohorts but there was a borderline inverse association in pooled case-control studies (past versus never OR = 0.70 and 95% CI 0.4–1.0, current versus never OR = 0.71 and 95% CI 0.5–1.0) [98]. Moreover, no dose-response association was found between OC use and risk of RA in this meta-analysis. These results highlighted a possible recall bias in case-control studies.
In addition, a recent case-control study reported an inverse association between OC use (ever, past, and >7 years versus never) and ACPA-positive RA (Table 2) [87], with a possible combined SE-OC effect on the risk of RA [90].
Past but not current menopausal therapy (MHT) was positively associated with RA risk in the Iowa Women’s Health Study (IWHS) and the Nurses’ Health Study (NHS) I cohorts (Table 2) as compared with never use [77,78]. However, a more recent analysis of the NHSs studies found a positive association between current MHT use (versus never HR = 1.4, 95% CI 1.1–1.9) and seropositive RA but only in the NHS I, whereas not in the NHS II or when pooling NHS I and II [89]. In the pooled cohorts, a duration of eight years and more of MHT (versus never) was associated with an increased risk of seropositive RA.
In case-control studies, MHT has not been associated with RA risk altogether, although current use of combined MHT has been inversely associated with ACPA-positive RA in menopausal women aged 50–59 with no effect of duration [99] (Table 2).
Thus, studies on OC or MHT and the risk of RA led to controversial results, potentially because of methodological issues (potential recall bias in case-control studies, insufficient accounting for confounders), changes in prescription of OCs and MHT over the past decades, and assessment of hormonal treatments as ever/never use, while analyses of durations and doses could lead to more precise estimates.
Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AI), used as a complementary treatment of breast cancers with positive estrogen receptors, reduce the endogenous production of estrogens after menopause. A study from the American national breast cancer database suggested dose-dependent associations between SERMs and AI and RA onset in women with a history of breast cancer (Table 2) [91]. The impact of AI would be stronger than tamoxifen on RA risk [92].

5. Diet

Many food components and beverages have been investigated in relation to RA risk in case-control and cohort studies. Several underlying mechanisms have been suggested, including the antioxidant effect of food, or the impact of diet on the gut microbiota, the involvement of which in RA pathophysiology has been suggested in different studies [100].
However, many studies regarding food have shown conflicting results. Some associations might be restricted to some populations, i.e., younger women, or ever-smokers. Table 3 summarizes results from selected cohorts and case-control studies, regarding the association between diet and the risk of RA.
Table 3. Selected case-control and cohort studies on diet and the risk for rheumatoid arthritis.

5.1. Fish Consumption

Fish consumption has been thought to be associated with a reduced risk of RA, but different studies have led to conflicting results. Potential mechanisms involve omega-3 fatty acids, which have been suggested to lower the risk of developing ACPAs and to prevent the onset of inflammatory arthritis once ACPAs are present [127]. In a case-control study, Shapiro et al. reported a lower risk of incident RA associated with high consumption of broiled and baked fish dishes [102]. However, this association was not found with other fish dishes.
Nevertheless, no association was found in four prospective cohort studies and three other case-control studies [101,104,105,106,108,109]. In a meta-analysis including 174,701 participants, Di Giuseppe et al. reported a borderline association between fish intake and the risk of RA (≥1 serving/week as compared with <1, RR 0.71, 95% CI 0.48–1.04).
More recently, in the NHSs I and II, Sparks et al. reported an increased risk of RA associated with fish consumption among women aged 55 and over [110]. However, they identified an interaction between smoking and fish consumption in that ever smokers with frequent fish consumption had only a modestly increased risk of RA as compared with a very high risk in ever-smokers with infrequent fish intakes.
Altogether, the literature regarding a potential association between fish consumption and RA risk is limited and does not allow us to state preventive advice. Potential benefit could be restricted to some high-risk populations, such as ever-smokers.

5.2. Olive Oil, Fruit, and Vegetables

Olive oil and its antioxidant effect have been shown to be beneficial for different health issues, such as cardiovascular diseases and cancers. Olive oil consumption has been associated with a lower risk of RA in two case-control studies [101,103]. However, two prospective cohort studies failed to report such inverse association [104,111].
Regarding fruit and vegetable consumption, two case-control studies reported an inverse association, with high consumptions of cooked vegetables (OR 0.39 for quartile 4 as compared with quartile 1, 95% CI 0.20–0.77, Ptrend = 0.001) [103], or fruit (OR 0.7 for tertile 3 versus tertile 1, 95% CI 0.4–1.3, Ptrend = 0.03) [112]. However, recent case-control and cohort studies failed to find any association [104,109,111]. Thus, available evidence is insufficient to recommend fruit and vegetable consumption to reduce RA risk.

5.3. Meat Consumption

Although an increased intake of red meat could be associated with cancer and cardiovascular risks, there is little evidence for a role in RA risk.
Pattison et al. [112] reported the first prospective investigation of red meat and risk for inflammatory polyarthritis and concluded that higher intakes of both red meat and protein increased the risk for inflammatory polyarthritis. However, they acknowledged that it remained unclear whether the observed associations were causative or whether meat consumption was a marker for other lifestyle factors. Since then, many different prospective cohort studies have investigated meat (overall, processed meat, poultry, and red meat), and have shown no association with the risk of RA [104,105,108,111,113].

5.4. Coffee, Tea, and Beverages

Over the last decades, many studies have investigated a potential link between consumption of coffee, tea, and other beverages and the risk of RA.
In a cross-sectional study [114], consumption of ≥four cups of coffee per day was associated with an increased risk of RF-positive RA (RR 2.20, 95% CI 1.13–4.27). Associations were similar with decaffeinated coffee (RR 2.64, 95% CI 1.46–4.79), especially among RF-positive patients [115]. Associations remained after adjustment for smoking status. Although those results were not reproducibly found in other publications [104,116,118], a meta-analysis of five studies reported a positive association between coffee consumption and RA risk (RR 2.43, 95% CI 1.06–5.55); the association was restricted to RF-positive RA (RR 1.33, 95% CI 1.16–1.52), but not with RF-negative RA (RR 1.09, 95% CI 0.88–1.35), suggesting potentially different underlying mechanisms [117].
Regarding tea consumption, the consumption of three cups or more per day has been associated with a lower risk of RA in one prospective study (RR 0.39, 95% CI 0.16–0.95) [115], but not confirmed in other prospective studies and in a meta-analysis [115,117].
A moderate consumption of alcohol has been found inversely associated with RA in several studies [119,120,121]. In the Swedish Mammography Cohort, Di Giuseppe et al. reported a statically significant 37% decrease in the risk of RA among women who drank four or more glasses of alcohol per week as compared with women who drank one glass or less (RR 0.63, 95% CI 0.42–0.96) [119]. In the NHSs I and II, Lu et al. also reported an inverse association between moderate alcohol consumption (5–10 g/day) as compared with no use (HR 0.78, 95% CI 0.61–1.00), this association being stronger for seropositive RA cases. Those results were confirmed in a meta-analysis involving 195,095 participants including 1878 RA cases, reporting an inverse association between low to moderate alcohol consumption and RA risk (RR 0.86, 95% CI 0.78–0.94), and providing some evidence of a nonlinear inverse relationship [120]. Recently, in the Swedish Epidemiologic Investigations of RA (EIRA) involving 3353 cases and 2836 matched controls, Hedström et al. reported a dose-dependent inverse association between low and moderate alcohol and RA risk as compared with no consumption (OR 0.57, 95% CI 0.49–0.66 and OR 0.49, 95% CI 0.41–0.58, respectively) [123]. Interestingly, non-drinking and the presence of HLA-DRB1 SE interacted to increase the risk for ACPA-positive RA, independent of smoking habits. However, physicians should consider the potential risks of alcohol before providing recommendations.
Finally, some studies have suggested an increased risk of RA with the consumption of sugar-sweetened soda, sometimes limited to seropositive RA (HR 1.63, 95% CI 1.15–2.30) [122].

5.5. Dietary Patterns

Recently, dietary pattern analysis has emerged as an alternative approach for examining the relationship between individual food items and the risk of disease. Indeed, because of the complexity of dietary habits and the interactions among foods and nutrients, examining the overall effect of diet, using dietary patterns derived from factor or cluster analysis, or dietary quality indices, could be a more realistic approach for investigating the risk of disease [128].
The Mediterranean diet (MD), widespread in Southern European countries, mainly consists of olive oil, cereal products, fresh or dried fruit and vegetables, nuts, fish, and a moderate amount of dairy, meat, and wine. This diet has been associated with significant reductions of overall mortality, as well as cardiovascular and neoplastic diseases [129]. Four studies have investigated the association between the MD and RA risk. In a Swedish nested case-control study, Sundström et al. found no association between the MD score and RA, although there was some non-statistically significant risk reduction among smokers [108]. More recently, a case-control study from the Swedish Epidemiological Investigation of RA reported an inverse association between the MD score and RA risk (OR 0.79, 95% CI 0.65–0.96) [125]. In the NHSs I and II, Hu et al. did not find any association between the alternate MD score (which does not include dairy products) and the risk of RA. However, those results might only apply to American women, whose dietary habits could differ from those of European countries [109]. Our team investigated the association between the MD and RA risk in the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle générale de l’Éducation nationale) cohort study of French women [111]. There was no association overall, but in ever-smokers, there was a significant trend towards a reduced risk of RA with a higher MD score. We hypothesized that the pro-oxidant effect of smoking could be balanced by the antioxidant effect of the MD.
Other dietary patterns have also been investigated such as diet quality, evaluated by the 2010 Alternative Healthy Index (AHAI-2010), which is a dietary quality score based on recent dietary guidelines for Americans, and is composed of 11 foods and nutrients that have been consistently inversely associated with risk of chronic diseases. In the NHS I and II, Hu et al. suggested that a long-term adherence to a healthy dietary pattern may reduce RA risk in women, particularly the risk of a seropositive RA diagnosis before the age of 55 years [124].
In addition, Sparks et al. investigated, in the same cohort, the associations among the Empirical Dietary Inflammatory Pattern (EDIP), including 18 anti- and pro-inflammatory food/beverage groups weighted by correlations with plasma inflammatory biomarkers [126]. Among women ≤55 years, increasing EDIP was associated with an increased risk of RA, and specifically seropositive RA. However, no association was found among women over 55 years old.

6. Conclusions

To date, smoking has been reproducibly demonstrated to trigger the emergence of RA, particularly in genetically predisposed individuals.
Regarding other inhalants, silica is the most robust non-smoking inhalant risk factor for RA with potential interaction with smoking and both would share the same pulmonary mucosal and systemic inflammation hypothesis. The literature is sparse or conflicting for other inhalants such as pesticides, other occupational inhalants, and air pollution because of difficulties in precisely measuring the level of exposure. To establish an independent relationship with RA, future studies investigating the association between inhalants and RA need to carefully account for timing of exposures and smoking duration and intensity (and not only smoking status) in the analyses.
Despite numerous studies investigating potential associations among individual reproductive factors and RA risk, the role of female hormones on the risk of RA remains unclear. Bias and methodological issues (including failure to adjust on smoking) could explain some discrepancies. Each lifetime reproductive event is associated with changes in hormonal levels, either increased (early menarche, late menopause, parity, PMH, and oral contraception use) or decreased (postpartum period, early menopause, late menarche, and anti-estrogen agent treatment). Assessing cumulative hormonal exposures, and taking into account lifetime reproductive events, may be an interesting approach to study female hormonal exposures.
There have been numerous studies that have investigated the association between diet and RA, and many of them have shown conflicting results. A high consumption of coffee seems to be associated with an increased risk of RA, and a moderate consumption of alcohol is inversely associated with the risk of RA, there is less evidence regarding other food groups. However, some associations could be restricted to some populations (≤55 year-old women, ever-smokers) or be limited to seropositive RA. Nevertheless, studying associations among RA and some dietary patterns, such as inflammatory dietary index, a Mediterranean diet, or diet quality indices, might be more accurate, and some associations among those patterns and RA risk have been found. These results could be used for individuals at high risk of developing RA (i.e., RA relatives or subjects with ACPA positivity) who could modify their diets in addition to correcting major risk factors such as smoking.

Author Contributions

Conceptualization, C.S., Y.N. and R.S.; methodology, C.S., Y.N. and R.S.; resources, C.S., Y.N. and R.S.; data curation, C.S., Y.N. and R.S.; writing—original draft preparation, C.S., Y.N. and R.S.; writing—review and editing, C.S., Y.N. and R.S.; supervision, M.-C.B.-R. and R.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Nielen, M.M.J.; van Schaardenburg, D.; Reesink, H.W.; van de Stadt, R.J.; van der Horst-Bruinsma, I.E.; de Koning, M.H.M.T.; Habibuw, M.R.; Vandenbroucke, J.P.; Dijkmans, B.A.C. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum. 2004, 50, 380–386. [Google Scholar] [CrossRef] [PubMed]
  2. Alpízar-Rodríguez, D.; Pluchino, N.; Canny, G.; Gabay, C.; Finckh, A. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology 2017, 56, 1254–1263. [Google Scholar] [CrossRef] [PubMed]
  3. GEO-RA Group. Latitude gradient influences the age of onset of rheumatoid arthritis: A worldwide survey. Clin. Rheumatol. 2017, 36, 485–497. [Google Scholar] [CrossRef] [PubMed]
  4. Vieira, V.M.; Hart, J.E.; Webster, T.F.; Weinberg, J.; Puett, R.; Laden, F.; Costenbader, K.H.; Karlson, E.W. Association between residences in U.S. northern latitudes and rheumatoid arthritis: A spatial analysis of the Nurses’ Health Study. Environ. Health Perspect. 2010, 118, 957–961. [Google Scholar] [CrossRef] [PubMed]
  5. Bengtsson, C.; Nordmark, B.; Klareskog, L.; Lundberg, I.; Alfredsson, L. EIRA Study Group Socioeconomic status and the risk of developing rheumatoid arthritis: Results from the Swedish EIRA study. Ann. Rheum. Dis. 2005, 64, 1588–1594. [Google Scholar] [CrossRef] [PubMed]
  6. Di Giuseppe, D.; Discacciati, A.; Orsini, N.; Wolk, A. Cigarette smoking and risk of rheumatoid arthritis: A dose-response meta-analysis. Arthritis Res. Ther. 2014, 16, R61. [Google Scholar] [CrossRef]
  7. Costenbader, K.H.; Feskanich, D.; Mandl, L.A.; Karlson, E.W. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am. J. Med. 2006, 119, e1–e9. [Google Scholar] [CrossRef]
  8. Stolt, P.; Bengtsson, C.; Nordmark, B.; Lindblad, S.; Lundberg, I.; Klareskog, L.; Alfredsson, L. Quantification of the influence of cigarette smoking on rheumatoid arthritis: Results from a population based case-control study, using incident cases. Ann. Rheum. Dis. 2003, 62, 835–841. [Google Scholar] [CrossRef]
  9. Criswell, L.A.; Merlino, L.A.; Cerhan, J.R.; Mikuls, T.R.; Mudano, A.S.; Burma, M.; Folsom, A.R.; Saag, K.G. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: Results from the Iowa Women’s Health Study. Am. J. Med. 2002, 112, 465–471. [Google Scholar] [CrossRef]
  10. Di Giuseppe, D.; Orsini, N.; Alfredsson, L.; Askling, J.; Wolk, A. Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women. Arthritis Res. Ther. 2013, 15, R56. [Google Scholar] [CrossRef]
  11. Voigt, L.F.; Koepsell, T.D.; Nelson, J.L.; Dugowson, C.E.; Daling, J.R. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis. Epidemiol. Camb. Mass 1994, 5, 525–532. [Google Scholar]
  12. Hutchinson, D.; Shepstone, L.; Moots, R.; Lear, J.T.; Lynch, M.P. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann. Rheum. Dis. 2001, 60, 223–227. [Google Scholar] [CrossRef] [PubMed]
  13. Reckner Olsson, A.; Skogh, T.; Wingren, G. Comorbidity and lifestyle, reproductive factors, and environmental exposures associated with rheumatoid arthritis. Ann. Rheum. Dis. 2001, 60, 934–939. [Google Scholar] [CrossRef]
  14. Pedersen, M.; Jacobsen, S.; Klarlund, M.; Pedersen, B.V.; Wiik, A.; Wohlfahrt, J.; Frisch, M. Environmental risk factors differ between rheumatoid arthritis with and without auto-antibodies against cyclic citrullinated peptides. Arthritis Res. Ther. 2006, 8, R133. [Google Scholar] [CrossRef] [PubMed]
  15. Mikuls, T.R.; Sayles, H.; Yu, F.; Levan, T.; Gould, K.A.; Thiele, G.M.; Conn, D.L.; Jonas, B.L.; Callahan, L.F.; Smith, E.; et al. Associations of cigarette smoking with rheumatoid arthritis in African Americans. Arthritis Rheum. 2010, 62, 3560–3568. [Google Scholar] [CrossRef]
  16. Yahya, A.; Bengtsson, C.; Lai, T.C.; Larsson, P.T.; Mustafa, A.N.; Abdullah, N.A.; Muhamad, N.; Hussein, H.; Klareskog, L.; Alfredsson, L.; et al. Smoking is associated with an increased risk of developing ACPA-positive but not ACPA-negative rheumatoid arthritis in Asian populations: Evidence from the Malaysian MyEIRA case-control study. Mod. Rheumatol. 2012, 22, 524–531. [Google Scholar] [CrossRef]
  17. Hedström, A.K.; Stawiarz, L.; Klareskog, L.; Alfredsson, L. Smoking and susceptibility to rheumatoid arthritis in a Swedish population-based case-control study. Eur. J. Epidemiol. 2018, 33, 415–423. [Google Scholar] [CrossRef]
  18. Liu, X.; Tedeschi, S.K.; Barbhaiya, M.; Leatherwood, C.L.; Speyer, C.B.; Lu, B.; Costenbader, K.H.; Karlson, E.W.; Sparks, J.A. Impact and Timing of Smoking Cessation on Reducing Risk of Rheumatoid Arthritis Among Women in the Nurses’ Health Studies. Arthritis Care Res. 2019, 71, 914–924. [Google Scholar] [CrossRef]
  19. Källberg, H.; Ding, B.; Padyukov, L.; Bengtsson, C.; Rönnelid, J.; Klareskog, L.; Alfredsson, L. Smoking is a major preventable risk factor for Rheumatoid arthritis Estimations of risks after various exposures to cigarette smoke. Ann. Rheum. Dis. 2011, 70, 508–511. [Google Scholar] [CrossRef]
  20. Van der Helm-van Mil, A.H.M.; Verpoort, K.N.; Breedveld, F.C.; Huizinga, T.W.J.; Toes, R.E.M.; de Vries, R.R.P. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006, 54, 1117–1121. [Google Scholar] [CrossRef]
  21. Karlson, E.W.; Chang, S.-C.; Cui, J.; Chibnik, L.B.; Fraser, P.A.; De Vivo, I.; Costenbader, K.H. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann. Rheum. Dis. 2010, 69, 54–60. [Google Scholar] [CrossRef] [PubMed]
  22. Linn-Rasker, S.P.; van der Helm-van Mil, A.H.M.; van Gaalen, F.A.; Kloppenburg, M.; de Vries, R.R.P.; le Cessie, S.; Breedveld, F.C.; Toes, R.E.M.; Huizinga, T.W.J. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann. Rheum. Dis. 2006, 65, 366–371. [Google Scholar] [CrossRef] [PubMed]
  23. Padyukov, L.; Silva, C.; Stolt, P.; Alfredsson, L.; Klareskog, L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004, 50, 3085–3092. [Google Scholar] [CrossRef] [PubMed]
  24. Lee, H.-S.; Irigoyen, P.; Kern, M.; Lee, A.; Batliwalla, F.; Khalili, H.; Wolfe, F.; Lum, R.F.; Massarotti, E.; Weisman, M.; et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: A mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 2007, 56, 1745–1753. [Google Scholar] [CrossRef] [PubMed]
  25. Klareskog, L.; Stolt, P.; Lundberg, K.; Källberg, H.; Bengtsson, C.; Grunewald, J.; Rönnelid, J.; Erlandsson Harris, H.; Ulfgren, A.-K.; Rantapää-Dahlqvist, S.; et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006, 54, 38–46. [Google Scholar] [CrossRef]
  26. Holers, V.M.; Demoruelle, M.K.; Kuhn, K.A.; Buckner, J.H.; Robinson, W.H.; Okamoto, Y.; Norris, J.M.; Deane, K.D. Rheumatoid arthritis and the mucosal origins hypothesis: Protection turns to destruction. Nat. Rev. Rheumatol. 2018, 14, 542–557. [Google Scholar] [CrossRef]
  27. Sparks, J.A.; Karlson, E.W. The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis. Curr. Rheumatol. Rep. 2016, 18, 15. [Google Scholar] [CrossRef]
  28. Catrina, A.I.; Ytterberg, A.J.; Reynisdottir, G.; Malmström, V.; Klareskog, L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat. Rev. Rheumatol. 2014, 10, 645–653. [Google Scholar] [CrossRef]
  29. Deane, K.D.; Demoruelle, M.K.; Kelmenson, L.B.; Kuhn, K.A.; Norris, J.M.; Holers, V.M. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 2017, 31, 3–18. [Google Scholar] [CrossRef]
  30. Lee, Y.H.; Rho, Y.H.; Choi, S.J.; Ji, J.D.; Song, G.G.; Nath, S.K.; Harley, J.B. The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. Rheumatology 2007, 46, 49–56. [Google Scholar] [CrossRef]
  31. Costenbader, K.H.; Chang, S.-C.; De Vivo, I.; Plenge, R.; Karlson, E.W. Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: Evidence of gene-environment interactions with heavy cigarette smoking. Arthritis Res. Ther. 2008, 10, R52. [Google Scholar] [CrossRef] [PubMed]
  32. Michou, L.; Teixeira, V.H.; Pierlot, C.; Lasbleiz, S.; Bardin, T.; Dieudé, P.; Prum, B.; Cornélis, F.; Petit-Teixeira, E. Associations between genetic factors, tobacco smoking and autoantibodies in familial and sporadic rheumatoid arthritis. Ann. Rheum. Dis. 2008, 67, 466–470. [Google Scholar] [CrossRef] [PubMed]
  33. Mahdi, H.; Fisher, B.A.; Källberg, H.; Plant, D.; Malmström, V.; Rönnelid, J.; Charles, P.; Ding, B.; Alfredsson, L.; Padyukov, L.; et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated α-enolase in the etiology of rheumatoid arthritis. Nat. Genet. 2009, 41, 1319–1324. [Google Scholar] [CrossRef] [PubMed]
  34. Johansson, M.; Arlestig, L.; Hallmans, G.; Rantapää-Dahlqvist, S. PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res. Ther. 2006, 8, R19. [Google Scholar] [CrossRef] [PubMed]
  35. Salliot, C.; Dawidowicz, K.; Lukas, C.; Guedj, M.; Paccard, C.; Benessiano, J.; Dougados, M.; Nicaise, P.; Meyer, O.; Dieudé, P. PTPN22 R620W genotype-phenotype correlation analysis and gene-environment interaction study in early rheumatoid arthritis: Results from the ESPOIR cohort. Rheumatology 2011, 50, 1802–1808. [Google Scholar] [CrossRef]
  36. Kochi, Y.; Thabet, M.M.; Suzuki, A.; Okada, Y.; Daha, N.A.; Toes, R.E.M.; Huizinga, T.W.J.; Myouzen, K.; Kubo, M.; Yamada, R.; et al. PADI4 polymorphism predisposes male smokers to rheumatoid arthritis. Ann. Rheum. Dis. 2011, 70, 512–515. [Google Scholar] [CrossRef]
  37. Hedström, A.K.; Klareskog, L.; Alfredsson, L. Exposure to passive smoking and rheumatoid arthritis risk: Results from the Swedish EIRA study. Ann. Rheum. Dis. 2018, 77, 970–972. [Google Scholar] [CrossRef]
  38. Kronzer, V.L.; Crowson, C.S.; Sparks, J.A.; Vassallo, R.; Davis, J.M. Investigating Asthma, Allergic Disease, Passive Smoke Exposure, and Risk of Rheumatoid Arthritis. Arthritis Rheumatol. 2019, 71, 1217–1224. [Google Scholar] [CrossRef]
  39. Seror, R.; Henry, J.; Gusto, G.; Aubin, H.-J.; Boutron-Ruault, M.-C.; Mariette, X. Passive smoking in childhood increases the risk of developing rheumatoid arthritis. Rheumatology 2019, 58, 1154–1162. [Google Scholar] [CrossRef]
  40. Jaakkola, J.J.K.; Gissler, M. Maternal smoking in pregnancy as a determinant of rheumatoid arthritis and other inflammatory polyarthropathies during the first 7 years of life. Int. J. Epidemiol. 2005, 34, 664–671. [Google Scholar] [CrossRef]
  41. Crowson, C.S.; Matteson, E.L.; Myasoedova, E.; Michet, C.J.; Ernste, F.C.; Warrington, K.J.; Davis, J.M.; Hunder, G.G.; Therneau, T.M.; Gabriel, S.E. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011, 63, 633–639. [Google Scholar] [CrossRef] [PubMed]
  42. Klockars, M.; Koskela, R.S.; Järvinen, E.; Kolari, P.J.; Rossi, A. Silica exposure and rheumatoid arthritis: A follow up study of granite workers 1940-81. Br. Med. J. Clin. Res. Ed. 1987, 294, 997–1000. [Google Scholar] [CrossRef] [PubMed]
  43. Turner, S.; Cherry, N. Rheumatoid arthritis in workers exposed to silica in the pottery industry. Occup. Environ. Med. 2000, 57, 443–447. [Google Scholar] [CrossRef] [PubMed]
  44. Olsson, A.R.; Skogh, T.; Axelson, O.; Wingren, G. Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup. Environ. Med. 2004, 61, 233–238. [Google Scholar] [CrossRef] [PubMed]
  45. Stolt, P.; Källberg, H.; Lundberg, I.; Sjögren, B.; Klareskog, L.; Alfredsson, L. Silica exposure is associated with increased risk of developing rheumatoid arthritis: Results from the Swedish EIRA study. Ann. Rheum. Dis. 2005, 64, 582–586. [Google Scholar] [CrossRef]
  46. Stolt, P.; Yahya, A.; Bengtsson, C.; Källberg, H.; Rönnelid, J.; Lundberg, I.; Klareskog, L.; Alfredsson, L. EIRA Study Group Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann. Rheum. Dis. 2010, 69, 1072–1076. [Google Scholar] [CrossRef]
  47. Yahya, A.; Bengtsson, C.; Larsson, P.; Too, C.L.; Mustafa, A.N.; Abdullah, N.A.; Muhamad, N.A.; Klareskog, L.; Murad, S.; Alfredsson, L. Silica exposure is associated with an increased risk of developing ACPA-positive rheumatoid arthritis in an Asian population: Evidence from the Malaysian MyEIRA case-control study. Mod. Rheumatol. 2014, 24, 271–274. [Google Scholar] [CrossRef]
  48. Blanc, P.D.; Järvholm, B.; Torén, K. Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers. Am. J. Med. 2015, 128, 1094–1101. [Google Scholar] [CrossRef]
  49. Ilar, A.; Gustavsson, P.; Wiebert, P.; Alfredsson, L. Occupational exposure to organic dusts and risk of developing rheumatoid arthritis: Findings from a Swedish population-based case-control study. RMD Open 2019, 5, e001049. [Google Scholar] [CrossRef]
  50. Schmajuk, G.; Trupin, L.; Yelin, E.; Blanc, P.D. Prevalence of Arthritis and Rheumatoid Arthritis in Coal Mining Counties of the United States. Arthritis Care Res. 2019, 71, 1209–1215. [Google Scholar] [CrossRef]
  51. Too, C.L.; Muhamad, N.A.; Ilar, A.; Padyukov, L.; Alfredsson, L.; Klareskog, L.; Murad, S.; Bengtsson, C. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: Results from a Malaysian population-based case–control study. Ann. Rheum. Dis. 2016, 75, 997–1002. [Google Scholar] [CrossRef] [PubMed]
  52. Sverdrup, B.; Källberg, H.; Bengtsson, C.; Lundberg, I.; Padyukov, L.; Alfredsson, L.; Klareskog, L. Epidemiological Investigation of Rheumatoid Arthritis Study Group Association between occupational exposure to mineral oil and rheumatoid arthritis: Results from the Swedish EIRA case-control study. Arthritis Res. Ther. 2005, 7, R1296–R1303. [Google Scholar] [CrossRef] [PubMed]
  53. Hjuler Boudigaard, S.; Stokholm, Z.A.; Vestergaard, J.M.; Mohr, M.S.; Søndergaard, K.; Torén, K.; Schlünssen, V.; Kolstad, H.A. A follow-up study of occupational styrene exposure and risk of autoimmune rheumatic diseases. Occup. Environ. Med. 2020, 77, 64–69. [Google Scholar] [CrossRef] [PubMed]
  54. Meyer, A.; Sandler, D.P.; Beane Freeman, L.E.; Hofmann, J.N.; Parks, C.G. Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study. Environ. Health Perspect. 2017, 125. [Google Scholar] [CrossRef]
  55. Parks, C.G.; Hoppin, J.A.; De Roos, A.J.; Costenbader, K.H.; Alavanja, M.C.; Sandler, D.P. Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures. Environ. Health Perspect. 2016, 124, 1728–1734. [Google Scholar] [CrossRef]
  56. De Roos, A.J.; Cooper, G.S.; Alavanja, M.C.; Sandler, D.P. Rheumatoid Arthritis among Women in the Agricultural Health Study: Risk Associated with Farming Activities and Exposures. Ann. Epidemiol. 2005, 15, 762–770. [Google Scholar] [CrossRef]
  57. Parks, C.G.; D’Aloisio, A.A.; Sandler, D.P. Childhood Residential and Agricultural Pesticide Exposures in Relation to Adult-Onset Rheumatoid Arthritis in Women. Am. J. Epidemiol. 2018, 187, 214–223. [Google Scholar] [CrossRef]
  58. Parks, C.G.; Meyer, A.; Beane Freeman, L.E.; Hofmann, J.N.; Sandler, D.P. Farming tasks and the development of rheumatoid arthritis in the agricultural health study. Occup. Environ. Med. 2019, 76, 243–249. [Google Scholar] [CrossRef]
  59. Ilar, A.; Alfredsson, L.; Wiebert, P.; Klareskog, L.; Bengtsson, C. Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case–Control Study. Arthritis Care Res. 2018, 70, 499–509. [Google Scholar] [CrossRef]
  60. Reckner Olsson, Å.; Skogh, T.; Wingren, G. Occupational determinants for rheumatoid arthritis. Scand. J. Work. Environ. Health 2000, 26, 243–249. [Google Scholar] [CrossRef]
  61. Cappelletti, R.; Ceppi, M.; Claudatus, J.; Gennaro, V. Health status of male steel workers at an electric arc furnace (EAF) in Trentino, Italy. J. Occup. Med. Toxicol. Lond. Engl. 2016, 11, 7. [Google Scholar] [CrossRef]
  62. Lundberg, I.; Alfredsson, L.; Plato, N.; Sverdrup, B.; Klareskog, L.; Kleinau, S. Occupation, Occupational Exposure to Chemicals and Rheumatological Disease: A register based cohort study. Scand. J. Rheumatol. 1994, 23, 305–310. [Google Scholar] [CrossRef] [PubMed]
  63. Noonan, C.W.; Pfau, J.C.; Larson, T.C.; Spence, M.R. Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ. Health Perspect. 2006, 114, 1243–1247. [Google Scholar] [CrossRef] [PubMed]
  64. Jones, K.A.; Smith, B.; Granado, N.S.; Boyko, E.J.; Gackstetter, G.D.; Ryan, M.A.K.; Phillips, C.J.; Smith, T.C. Millennium Cohort Study Team Newly reported lupus and rheumatoid arthritis in relation to deployment within proximity to a documented open-air burn pit in Iraq. J. Occup. Environ. Med. 2012, 54, 698–707. [Google Scholar] [CrossRef] [PubMed]
  65. Hart, J.E.; Laden, F.; Puett, R.C.; Costenbader, K.H.; Karlson, E.W. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ. Health Perspect. 2009, 117, 1065–1069. [Google Scholar] [CrossRef] [PubMed]
  66. De Roos, A.J.; Koehoorn, M.; Tamburic, L.; Davies, H.W.; Brauer, M. Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis. Environ. Health Perspect. 2014, 122, 1075–1080. [Google Scholar] [CrossRef]
  67. Shin, J.; Lee, J.; Lee, J.; Ha, E.-H. Association between Exposure to Ambient Air Pollution and Rheumatoid Arthritis in Adults. Int. J. Environ. Res. Public Health 2019, 16. [Google Scholar] [CrossRef]
  68. Hart, J.E.; Källberg, H.; Laden, F.; Costenbader, K.H.; Yanosky, J.D.; Klareskog, L.; Alfredsson, L.; Karlson, E.W. Ambient air pollution exposures and risk of rheumatoid arthritis. Arthritis Care Res. 2013, 65, 1190–1196. [Google Scholar] [CrossRef]
  69. Hart, J.E.; Källberg, H.; Laden, F.; Bellander, T.; Costenbader, K.H.; Holmqvist, M.; Klareskog, L.; Alfredsson, L.; Karlson, E.W. Ambient air pollution exposures and risk of rheumatoid arthritis: Results from the Swedish EIRA case-control study. Ann. Rheum. Dis. 2013, 72, 888–894. [Google Scholar] [CrossRef]
  70. Chang, K.-H.; Hsu, C.-C.; Muo, C.-H.; Hsu, C.Y.; Liu, H.-C.; Kao, C.-H.; Chen, C.-Y.; Chang, M.-Y.; Hsu, Y.-C. Air pollution exposure increases the risk of rheumatoid arthritis: A longitudinal and nationwide study. Environ. Int. 2016, 94, 495–499. [Google Scholar] [CrossRef]
  71. Vihlborg, P.; Bryngelsson, I.-L.; Andersson, L.; Graff, P. Risk of sarcoidosis and seropositive rheumatoid arthritis from occupational silica exposure in Swedish iron foundries: A retrospective cohort study. BMJ Open 2017, 7, e016839. [Google Scholar] [CrossRef] [PubMed]
  72. Zeng, P.; Chen, Z.; Klareskog, L.; Alfredsson, L.; Bengtsson, C.; Jiang, X. Amount of smoking, duration of smoking cessation and their interaction with silica exposure in the risk of rheumatoid arthritis among males: Results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. Ann. Rheum. Dis. 2018, 77, 1238–1241. [Google Scholar] [CrossRef] [PubMed]
  73. Koureas, M.; Rachiotis, G.; Tsakalof, A.; Hadjichristodoulou, C. Increased Frequency of Rheumatoid Arthritis and Allergic Rhinitis among Pesticide Sprayers and Associations with Pesticide Use. Int. J. Environ. Res. Public Health 2017, 14. [Google Scholar] [CrossRef] [PubMed]
  74. Parks, C.G.; Walitt, B.T.; Pettinger, M.; Chen, J.-C.; de Roos, A.J.; Hunt, J.; Sarto, G.; Howard, B.V. Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the Women’s Health Initiative Observational Study. Arthritis Care Res. 2011, 63, 184–194. [Google Scholar] [CrossRef]
  75. Li, X.; Sundquist, J.; Sundquist, K. Socioeconomic and occupational risk factors for rheumatoid arthritis: A nationwide study based on hospitalizations in Sweden. J. Rheumatol. 2008, 35, 986–991. [Google Scholar]
  76. Miller-Archie, S.A.; Izmirly, P.M.; Berman, J.R.; Brite, J.; Walker, D.J.; Dasilva, R.C.; Petrsoric, L.J.; Cone, J.E. Systemic Autoimmune Disease Among Adults Exposed to the September 11, 2001 Terrorist Attack. Arthritis Rheumatol. 2020, 72, 849–859. [Google Scholar] [CrossRef]
  77. Karlson, E.; Mandl, L.; Hankinson, S.; Grodstein, F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses’ Health Study. Arthritis Rheum. 2004, 50, 3458–3467. [Google Scholar] [CrossRef]
  78. Merlino, L.A.; Cerhan, J.R.; Criswell, L.A.; Mikuls, T.R.; Saag, K.G. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin. Arthritis Rheum. 2003, 33, 72–82. [Google Scholar] [CrossRef]
  79. Pikwer, M.; Bergström, U.; Nilsson, J.-Å.; Jacobsson, L.; Turesson, C. Early menopause is an independent predictor of rheumatoid arthritis. Ann. Rheum. Dis. 2012, 71, 378–381. [Google Scholar] [CrossRef]
  80. Jørgensen, K.T.; Pedersen, B.V.; Jacobsen, S.; Biggar, R.J.; Frisch, M. National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: A role for hyperemesis, gestational hypertension and pre-eclampsia? Ann. Rheum. Dis. 2010, 69, 358–363. [Google Scholar] [CrossRef]
  81. Guthrie, K.A.; Dugowson, C.E.; Voigt, L.F.; Koepsell, T.D.; Nelson, J.L. Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum. 2010, 62, 1842–1848. [Google Scholar] [CrossRef] [PubMed]
  82. Silman, A.; Kay, A.; Brennan, P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum. 1992, 35, 152–155. [Google Scholar] [CrossRef] [PubMed]
  83. Orellana, C.; Wedrén, S.; Källberg, H.; Holmqvist, M.; Karlson, E.W.; Alfredsson, L.; Bengtsson, C. EIRA Study Group Parity and the risk of developing rheumatoid arthritis: Results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Ann. Rheum. Dis. 2014, 73, 752–755. [Google Scholar] [CrossRef]
  84. Peschken, C.A.; Robinson, D.B.; Hitchon, C.A.; Smolik, I.; Hart, D.; Bernstein, C.N.; El-Gabalawy, H.S. Pregnancy and the risk of rheumatoid arthritis in a highly predisposed North American Native population. J. Rheumatol. 2012, 39, 2253–2260. [Google Scholar] [CrossRef]
  85. Adab, P.; Jiang, C.Q.; Rankin, E.; Tsang, Y.W.; Lam, T.H.; Barlow, J.; Thomas, G.N.; Zhang, W.S.; Cheng, K.K. Breastfeeding practice, oral contraceptive use and risk of rheumatoid arthritis among Chinese women: The Guangzhou Biobank Cohort Study. Rheumatology 2014, 53, 860–866. [Google Scholar] [CrossRef]
  86. Berglin, E.; Kokkonen, H.; Einarsdottir, E.; Agren, A.; Rantapää Dahlqvist, S. Influence of female hormonal factors, in relation to autoantibodies and genetic markers, on the development of rheumatoid arthritis in northern Sweden: A case-control study. Scand. J. Rheumatol. 2010, 39, 454–460. [Google Scholar] [CrossRef] [PubMed]
  87. Orellana, C.; Saevarsdottir, S.; Klareskog, L.; Karlson, E.W.; Alfredsson, L.; Bengtsson, C. Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: Results from the Swedish EIRA study. Ann. Rheum. Dis. 2017, 76, 1845–1852. [Google Scholar] [CrossRef] [PubMed]
  88. Harris, H.R.; Costenbader, K.H.; Mu, F.; Kvaskoff, M.; Malspeis, S.; Karlson, E.W.; Missmer, S.A. Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses’ Health Study II. Ann. Rheum. Dis. 2016, 75, 1279–1284. [Google Scholar] [CrossRef]
  89. Bengtsson, C.; Malspeis, S.; Orellana, C.; Sparks, J.A.; Costenbader, K.H.; Karlson, E.W. Association Between Menopausal Factors and the Risk of Seronegative and Seropositive Rheumatoid Arthritis: Results From the Nurses’ Health Studies. Arthritis Care Res. 2017, 69, 1676–1684. [Google Scholar] [CrossRef]
  90. Pedersen, M.; Jacobsen, S.; Garred, P.; Madsen, H.O.; Klarlund, M.; Svejgaard, A.; Pedersen, B.V.; Wohlfahrt, J.; Frisch, M. Strong combined gene-environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis: A nationwide case-control study in Denmark. Arthritis Rheum. 2007, 56, 1446–1453. [Google Scholar] [CrossRef]
  91. Chen, J.Y.; Ballou, S.P. The effect of antiestrogen agents on risk of autoimmune disorders in patients with breast cancer. J. Rheumatol. 2015, 42, 55–59. [Google Scholar] [CrossRef] [PubMed]
  92. Caprioli, M.; Carrara, G.; Sakellariou, G.; Silvagni, E.; Scirè, C.A. Influence of aromatase inhibitors therapy on the occurrence of rheumatoid arthritis in women with breast cancer: Results from a large population-based study of the Italian Society for Rheumatology. RMD Open 2017, 3, e000523. [Google Scholar] [CrossRef] [PubMed]
  93. Alpizar-Rodriguez, D.; Mueller, R.B.; Möller, B.; Dudler, J.; Ciurea, A.; Zufferey, P.; Kyburz, D.; Walker, U.A.; von Mühlenen, I.; Roux-Lombard, P.; et al. Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. Rheumatology 2017, 56, 1579–1585. [Google Scholar] [CrossRef] [PubMed]
  94. Wallenius, M.; Skomsvoll, J.F.; Irgens, L.M.; Salvesen, K.A.; Koldingsnes, W.; Mikkelsen, K.; Kaufmann, C.; Kvien, T.K. Postpartum onset of rheumatoid arthritis and other chronic arthritides: Results from a patient register linked to a medical birth registry. Ann. Rheum. Dis. 2010, 69, 332–336. [Google Scholar] [CrossRef]
  95. Ren, L.; Guo, P.; Sun, Q.-M.; Liu, H.; Chen, Y.; Huang, Y.; Cai, X.-J. Number of parity and the risk of rheumatoid arthritis in women: A dose-response meta-analysis of observational studies. J. Obstet. Gynaecol. Res. 2017, 43, 1428–1440. [Google Scholar] [CrossRef]
  96. Chen, H.; Wang, J.; Zhou, W.; Yin, H.; Wang, M. Breastfeeding and Risk of Rheumatoid Arthritis: A Systematic Review and Metaanalysis. J. Rheumatol. 2015, 42, 1563–1569. [Google Scholar] [CrossRef]
  97. Shigesi, N.; Kvaskoff, M.; Kirtley, S.; Feng, Q.; Fang, H.; Knight, J.C.; Missmer, S.A.; Rahmioglu, N.; Zondervan, K.T.; Becker, C.M. The association between endometriosis and autoimmune diseases: A systematic review and meta-analysis. Hum. Reprod. Update 2019, 25, 486–503. [Google Scholar] [CrossRef]
  98. Chen, Q.; Jin, Z.; Xiang, C.; Cai, Q.; Shi, W.; He, J. Absence of protective effect of oral contraceptive use on the development of rheumatoid arthritis: A meta-analysis of observational studies. Int. J. Rheum. Dis. 2014, 17, 725–737. [Google Scholar] [CrossRef]
  99. Orellana, C.; Saevarsdottir, S.; Klareskog, L.; Karlson, E.W.; Alfredsson, L.; Bengtsson, C. Postmenopausal hormone therapy and the risk of rheumatoid arthritis: Results from the Swedish EIRA population-based case-control study. Eur. J. Epidemiol. 2015, 30, 449–457. [Google Scholar] [CrossRef]
  100. Alpizar-Rodriguez, D.; Lesker, T.R.; Gronow, A.; Gilbert, B.; Raemy, E.; Lamacchia, C.; Gabay, C.; Finckh, A.; Strowig, T. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann. Rheum. Dis. 2019. [Google Scholar] [CrossRef]
  101. Linos, A.; Kaklamanis, E.; Kontomerkos, A.; Koumantaki, Y.; Gazi, S.; Vaiopoulos, G.; Tsokos, G.C.; Kaklamanis, P. The Effect of Olive Oil and Fish Consumption on Rheumatoid Arthritis—A Case Control Study. Scand. J. Rheumatol. 1991, 20, 419–426. [Google Scholar] [CrossRef] [PubMed]
  102. Shapiro, J.A.; Koepsell, T.D.; Voigt, L.F.; Dugowson, C.E.; Kestin, M.; Nelson, J.L. Diet and rheumatoid arthritis in women: A possible protective effect of fish consumption. Epidemiol. Camb. Mass 1996, 7, 256–263. [Google Scholar] [CrossRef] [PubMed]
  103. Linos, A.; Kaklamani, V.G.; Kaklamani, E.; Koumantaki, Y.; Giziaki, E.; Papazoglou, S.; Mantzoros, C.S. Dietary factors in relation to rheumatoid arthritis: A role for olive oil and cooked vegetables? Am. J. Clin. Nutr. 1999, 70, 1077–1082. [Google Scholar] [CrossRef] [PubMed]
  104. Pedersen, M.; Stripp, C.; Klarlund, M.; Olsen, S.F.; Tjønneland, A.M.; Frisch, M. Diet and risk of rheumatoid arthritis in a prospective cohort. J. Rheumatol. 2005, 32, 1249–1252. [Google Scholar]
  105. Benito-Garcia, E.; Feskanich, D.; Hu, F.B.; Mandl, L.A.; Karlson, E.W. Protein, iron, and meat consumption and risk for rheumatoid arthritis: A prospective cohort study. Arthritis Res. Ther. 2007, 9, R16. [Google Scholar] [CrossRef]
  106. Di Giuseppe, D.; Wallin, A.; Bottai, M.; Askling, J.; Wolk, A. Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: A prospective cohort study of women. Ann. Rheum. Dis. 2014, 73, 1949–1953. [Google Scholar] [CrossRef]
  107. Di Giuseppe, D.; Crippa, A.; Orsini, N.; Wolk, A. Fish consumption and risk of rheumatoid arthritis: A dose-response meta-analysis. Arthritis Res. Ther. 2014, 16, 446. [Google Scholar] [CrossRef]
  108. Sundström, B.; Johansson, I.; Rantapää-Dahlqvist, S. Diet and alcohol as risk factors for rheumatoid arthritis: A nested case–control study. Rheumatol. Int. 2015, 35, 533–539. [Google Scholar] [CrossRef]
  109. Hu, Y.; Costenbader, K.H.; Gao, X.; Hu, F.B.; Karlson, E.W.; Lu, B. Mediterranean diet and incidence of rheumatoid arthritis in women. Arthritis Care Res. 2015, 67, 597–606. [Google Scholar] [CrossRef]
  110. Sparks, J.A.; O’Reilly, É.J.; Barbhaiya, M.; Tedeschi, S.K.; Malspeis, S.; Lu, B.; Willett, W.C.; Costenbader, K.H.; Karlson, E.W. Association of fish intake and smoking with risk of rheumatoid arthritis and age of onset: A prospective cohort study. BMC Musculoskelet. Disord. 2019, 20, 2. [Google Scholar] [CrossRef]
  111. Nguyen, Y.; Salliot, C.; Gelot, A.; Gambaretti, J.; Mariette, X.; Boutron-Ruault, M.-C.; Seror, R. Mediterranean diet and risk of rheumatoid arthritis: Findings from the French E3N-EPIC cohort study. Arthritis Rheumatol. 2020. [Google Scholar] [CrossRef]
  112. Pattison, D.J.; Symmons, D.P.M.; Lunt, M.; Welch, A.; Luben, R.; Bingham, S.A.; Khaw, K.-T.; Day, N.E.; Silman, A.J. Dietary risk factors for the development of inflammatory polyarthritis: Evidence for a role of high level of red meat consumption. Arthritis Rheum. 2004, 50, 3804–3812. [Google Scholar] [CrossRef] [PubMed]
  113. Sundström, B.; Ljung, L.; Di Giuseppe, D. Consumption of Meat and Dairy Products Is Not Associated with the Risk for Rheumatoid Arthritis among Women: A Population-Based Cohort Study. Nutrients 2019, 11. [Google Scholar] [CrossRef] [PubMed]
  114. Heliovaara, M.; Aho, K.; Knekt, P.; Impivaara, O.; Reunanen, A.; Aromaa, A. Coffee consumption, rheumatoid factor, and the risk of rheumatoid arthritis. Ann. Rheum. Dis. 2000, 59, 631–635. [Google Scholar] [CrossRef]
  115. Mikuls, T.R.; Cerhan, J.R.; Criswell, L.A.; Merlino, L.; Mudano, A.S.; Burma, M.; Folsom, A.R.; Saag, K.G. Coffee, tea, and caffeine consumption and risk of rheumatoid arthritis: Results from the Iowa Women’s Health Study. Arthritis Rheum. 2002, 46, 83–91. [Google Scholar] [CrossRef]
  116. Karlson, E.W.; Mandl, L.A.; Aweh, G.N.; Grodstein, F. Coffee consumption and risk of rheumatoid arthritis. Arthritis Rheum. 2003, 48, 3055–3060. [Google Scholar] [CrossRef]
  117. Lee, Y.H.; Bae, S.-C.; Song, G.G. Coffee or tea consumption and the risk of rheumatoid arthritis: A meta-analysis. Clin. Rheumatol. 2014, 33, 1575–1583. [Google Scholar] [CrossRef]
  118. Lamichhane, D.; Collins, C.; Constantinescu, F.; Walitt, B.; Pettinger, M.; Parks, C.; Howard, B.V. Coffee and Tea Consumption in Relation to Risk of Rheumatoid Arthritis in the Women’s Health Initiative Observational Cohort. J. Clin. Rheumatol. 2019, 25, 127–132. [Google Scholar] [CrossRef]
  119. Di Giuseppe, D.; Alfredsson, L.; Bottai, M.; Askling, J.; Wolk, A. Long term alcohol intake and risk of rheumatoid arthritis in women: A population based cohort study. BMJ 2012, 345, e4230. [Google Scholar] [CrossRef]
  120. Jin, Z.; Xiang, C.; Cai, Q.; Wei, X.; He, J. Alcohol consumption as a preventive factor for developing rheumatoid arthritis: A dose-response meta-analysis of prospective studies. Ann. Rheum. Dis. 2014, 73, 1962–1967. [Google Scholar] [CrossRef]
  121. Lu, B.; Solomon, D.H.; Costenbader, K.H.; Karlson, E.W. Alcohol Consumption and Risk of Incident Rheumatoid Arthritis in Women: A Prospective Study. Arthritis Rheumatol. 2014, 66, 1998–2005. [Google Scholar] [CrossRef] [PubMed]
  122. Hu, Y.; Costenbader, K.H.; Gao, X.; Al-Daabil, M.; Sparks, J.A.; Solomon, D.H.; Hu, F.B.; Karlson, E.W.; Lu, B. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am. J. Clin. Nutr. 2014, 100, 959–967. [Google Scholar] [CrossRef] [PubMed]
  123. Hedström, A.K.; Hössjer, O.; Klareskog, L.; Alfredsson, L. Interplay between alcohol, smoking and HLA genes in RA aetiology. RMD Open 2019, 5, e000893. [Google Scholar] [CrossRef] [PubMed]
  124. Hu, Y.; Sparks, J.A.; Malspeis, S.; Costenbader, K.H.; Hu, F.B.; Karlson, E.W.; Lu, B. Long-term dietary quality and risk of developing rheumatoid arthritis in women. Ann. Rheum. Dis. 2017, 76, 1357–1364. [Google Scholar] [CrossRef] [PubMed]
  125. Johansson, K.; Askling, J.; Alfredsson, L.; Di Giuseppe, D. On behalf of the EIRA study group Mediterranean diet and risk of rheumatoid arthritis: A population-based case-control study. Arthritis Res. Ther. 2018, 20, 175. [Google Scholar] [CrossRef]
  126. Sparks, J.A.; Barbhaiya, M.; Tedeschi, S.K.; Leatherwood, C.L.; Tabung, F.K.; Speyer, C.B.; Malspeis, S.; Costenbader, K.H.; Karlson, E.W.; Lu, B. Inflammatory dietary pattern and risk of developing rheumatoid arthritis in women. Clin. Rheumatol. 2019, 38, 243–250. [Google Scholar] [CrossRef]
  127. Sparks, J.A.; Costenbader, K.H. Rheumatoid arthritis in 2017: Protective dietary and hormonal factors brought to light. Nat. Rev. Rheumatol. 2018, 14, 71–72. [Google Scholar] [CrossRef]
  128. Hu, F.B. Dietary pattern analysis: A new direction in nutritional epidemiology. Curr. Opin. Lipidol. 2002, 13, 3–9. [Google Scholar] [CrossRef]
  129. Sofi, F.; Macchi, C.; Abbate, R.; Gensini, G.F.; Casini, A. Mediterranean diet and health status: An updated meta-analysis and a proposal for a literature-based adherence score. Public Health Nutr. 2014, 17, 2769–2782. [Google Scholar] [CrossRef]

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