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Rheumatoid arthritis (RA) is a systemic autoimmune disease of connective tissue with a progressive course, manifested by joint inflammation (Eberhard et al., 2021, Frazzei et al., 2022). It typically affects the small joints of the hands and feet bilaterally, but it can also occur in other joints, where the inflamed synovium thickens and the joint area becomes tender, swollen and stiff, which makes movement difficult and leads to pain, destruction of bone and cartilage joints, and loss of function (Eberhard et al., 2021, Gerlag et al., 2012, Chen et al., 2015, Frazzei et al., 2022). The worldwide prevalence ranges from 0.4 to 1.3% (higher incidence in America and Europe, lower in Southeast Asia) and RA is included among the 50 most frequent diseases that contribute to global disability (Espinoza et al., 2021, Finckh et al., 2022, Frazzei et al., 2022) with a significant socioeconomic impact (Gerlag et al. al., 2012, Finckh et al., 2022). In Slovakia, RA affects about 26,000 adults, and the number of newly diagnosed cases increases annually by 1,300-1,600 patients (Grega and Kolar, 2024). The exact etiology of the disease is unknown, but over the past decade, research has made significant progress in identifying risk factors for the development of RA and has contributed to the current more effective treatment methods, which significantly improve the prognosis of patients (Romao and Fonseca, 2021). However, despite these advances, there is still a substantial gap in the management of the disease, many patients have difficulty achieving remission and RA problems such as functional disability, pain and fatigue persist, causing them various limitations and thus reducing the quality of life (Espinoza et al., 2021, Eberhard et al., 2021).

The European League Against Rheumatism (EULAR), which strives to improve the care of rheumatic patients, has defined the stages that precede RA as: genetic and environmental risk factors, systemic autoimmunity associated with RA, symptoms without clinical arthritis, and unclassified arthritis (Gerlag et al., 2012). For the sake of simplicity, we can divide the risk factors of RA into factors related to the host (patient) and environmental factors. Host factors can include genetic, epigenetic, hormonal, reproductive and neuroendocrinological factors, or others associated with patient comorbidities. Under environmental factors we can include smoking, diet and lifestyle, socio-economic factors, but also air pollution, microbiology, or infectious agents (Romao and Fonseca, 2021). Research assumes that around 30-66% of the development of RA is due to genetic susceptibility and 40-70% is caused by the influence of non-genetic facts (Arleevskaya et al., 2022, Scherer et al., 2020, Wells et al., 2020), therefore it is important to devote a deeper study of both types of factors contributing to the development of the disease, with special attention paid to factors that can be influenced.

Host Factors

Genetic risk factors

Genetic research has shown a significant hereditary component in RA (Frazzei et al., 2022). Family and twin studies reveal that monozygotic twins of RA patients have a 9-15% risk of developing RA, which is 4-fold higher compared to dizygotic twins and much higher than the general population (Romao and Fonseca, 2021). First-degree relatives have a 2-5-fold increased risk (Romao and Fonseca, 2021, Deane et al., 2017) and in addition, if the parents suffered from other autoimmune diseases (e.g. systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, or Hashimoto's thyroiditis), their offspring, regardless of gender, face a 1.5- to 3-fold higher risk of developing RA (Somers et al. al., 2013). The most significant genetic risk factors specific human leukocyte antigen (HLA) loci, such as HLA-DRB1, are strongly associated with RA, with risk varying by allele and ancestry, but may contribute to nearly 33% of RA risk (Frazzei et al., 2022).

Epigenetic risk factors

Epigenetics regulates gene transcription and is involved in the onset and progression of diseases, including RA, causing heritable changes in gene expression without altering DNA sequences (Romao and Fonseca, 2021). Epigenetic modifications, influenced by external factors such as diet and smoking, include DNA methylation, histone modification and microRNA (Romao and Fonseca, 2021, Yang et al., 2022). Studies have shown differential DNA methylation patterns in RA patients that affect genes involved in inflammation (Romao and Fonseca, 2021). However, research in this area is still in its infancy and requires further investigation to fully understand the progression of RA. While histone acetylation inhibitors show promising anti-inflammatory effects in the laboratory, their clinical efficacy requires validation (Yang et al., 2022). Deepening the knowledge about the epigenetic mechanisms of RA can help in the discovery of new diagnostic markers and therapeutic targets and thus improve RA management (Yang et al., 2022, Romao and Fonseca, 2021).

Hormonal, reproductive and neuroendocrine factors

The prevalence is approximately three times higher in females compared to males (Espinoza et al., 2021), with the ratio in younger patients being up to four times higher in females and in older patients this female to male ratio may be less than 2:1 (Finckh et al., 2022). In men, the prevalence increases after the age of 40, which also indicates that more than 50% of RA patients are older than 65 years (Nilsson et al., 2021). The ratio of incidence in women to men drops sharply after menopause, as in many other autoimmune diseases. Thus, women are more affected, especially during the reproductive period, when serum levels of the main sex hormones, 17β-estradiol and progesterone, are about 10 times higher in women than in men (compared to testosterone) (Biljsma and Hachulla, 2018). On the contrary, a problem-free pregnancy and breastfeeding is associated with a reduced probability of RA occurrence (Chen et al., 2015, Finckh et al., 2022, Deane et al., 2017).

Disorders of the neuroendocrine system, specifically the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system, play a significant role in the pathogenesis of RA (Romao and Fonseca, 2021). During systemic inflammation, these systems usually suppress inflammation through anti-inflammatory hormones and neurotransmitters. However, in RA, this regulation is disrupted, leading to a pro-inflammatory environment in the joints (Cutolo et al., 2007). Key mechanisms include a state of relative adrenal insufficiency, altered circadian rhythms of hormone secretion, and impaired local hormonal activity. In addition, changes in the sympathetic and sensory nervous system, such as loss of sympathetic nerve fibers and a shift to pro-inflammatory signaling, further contribute to chronic RA inflammation and synovitis (Romao and Fonseca, 2021).

Comorbidities

Another risk factor for RA is the presence of comorbidities. For the most part, comorbidities are investigated in already diagnosed patients (such as cardiovascular diseases, infections, osteoporosis), but research shows that some diseases such as post-traumatic stress disorder (PTSD), depression, allergies, respiratory and autoimmune diseases, as well as sleep disorders, on the contrary, contribute to the development of RA (Romao and Fonseca, 2021).

Regardless of gender, the presence of persistent psychological distress due to PTSD can lead to physiological abnormalities such as deregulation of the HPA axis, the autonomic nervous system, and the immune system. Decreased levels of cortisol have also been reported in PTSD patients, which can cause inflammatory-immune hyperactivity and accelerate the aging of immune cells. Such chronic immune dysregulation is the basis for the development of autoimmune diseases (Hsu et al., 2024, Frazzei et al., 2022). Another psychiatric diagnosis, which is often an associated comorbidity in RA patients with a prevalence of 9.5-46% (Espinoza et al., 2021), is also being investigated as a risk factor for the onset of RA (increases the risk by 28-65%), thus indicating a bidirectional relationship (Romao and Fonseca, 2021). Research shows that indicators of depression, specifically the use of antidepressants, are associated with a subsequent increased risk of seronegative RA, and this finding was not explained by measured lifestyle factors, such as smoking, BMI, diet, or regular exercise, before clinical manifestation (Sparks et al., 2021).

In addition to psychiatric comorbidities, current studies show an increased incidence of RA in the population suffering from atopy and allergy (e.g. asthma, allergic rhinitis, or atopic dermatitis), which was previously associated with a negative association with the risk of RA. Also, respiratory diseases, especially in non-smokers, are associated with an increased risk of both seropositive and seronegative RA (Romao and Fonseca, 2021). Non-rheumatological immune diseases identified in connection with the risk of RA outbreaks also include thyroid diseases, diabetes mellitus, alopecia areata, vitiligo, and multiple sclerosis (Romao and Fonseca, 2021). In addition to stress, sleep deprivation also causes an increase in the level of pro-inflammatory cytokines and thus contributes to the possible development of RA (Arleevskaya et al., 2022).

Environmental factors

Smoking and air pollution

Smoking tobacco products ranks among the most prominent environmental factors for the development of RA (Frazzei et al., 2022, Deane et al., 2017) and is currently thought to explain 20–30% of the total environmental risk (Romao and Fonseca, 2021, Deane et al., 2017). Moderate consumption of cigarettes is sufficient to influence the risk, but long-term exposure increases it and this risk is present even several years after quitting smoking (Frazzei et al., 2022). Specifically, it shows a linear increase in risk for current or heavy smokers, compared to occasional smokers or those who have stopped, where the risk of RA progressively decreased and after 20-30 years the risk returned to the level of non-smokers (Romao and Fonseca, 2021). Smoking causes citrulline autoimmunity in the lungs of genetically susceptible individuals and also triggers the production of rheumatoid factor (RF), which may explain the association found between smoking and seropositive RA (Frazzei et al., 2022).

Occupational exposure (e.g., in the mining, construction, or ceramic industries) also appears to be a risk factor for autoimmune diseases, and exposure to silica, textile, and other inorganic dust (e.g., asbestos, cement) has been found to increase the risk of RA (Frazzei et al., 2022, Romao and Fonseca, 2021). The recognition of the lungs as the main site of early pathogenic changes was one of the most significant breakthroughs for the understanding of the disease.

Microflora and infections

It has long been assumed that various infections can be a risk factor for the development of RA and a trend has been observed where the incidence of RA has been reduced in populations where health and hygienic conditions have improved. In recent years, oral and intestinal dysbiosis have started to be associated with participation in the etiology and pathogenesis of RA (Clemente et al., 2018, Finckh et al., 2022, Li and Wang, 2021, Potempa et al., 2017, Romao and Fonseca, 2021). Infections such as Epstein-Barr virus, parvovirus B19, rubella, or hepatitis B/C are associated with the development of RA, but the associations are inconsistent (Romao and Fonseca, 2021).

Periodontitis, which results from oral microbial dysbiosis, is associated with an increased risk of RA, and patients diagnosed with RA are also more likely to develop periodontitis. Both diseases share genetic and environmental risk factors, such as HLA-SE alleles, smoking, and diet, and lead to chronic inflammation, bone erosion, and tissue destruction (Potempa et al., 2017). Porphyromonas gingivalis, the main cause of periodontitis, has been specifically linked to RA mechanisms similar to those associated with smoking (Romao and Fonseca, 2021, Deane et al., 2017).

In recent years, significant interest has focused on the role of gut microflora in immune homeostasis and the development of diseases, including RA (Wells et al., 2020). Gut dysbiosis has been associated with RA, which is supported by animal studies demonstrating the microbial flora requirement for experimental arthritis and human studies reporting changes in gut microbiota composition in RA patients (Clemente et al., 2018, Li and Wang, 2021).

Diet and obesity

Daily consumption of sugar-sweetened sodas is associated with an increased risk of RA (up to 63% increased risk of seropositive RA) (Finckh et al., 2022, Mosalmanzadeh et al., 2020, Romao and Fonseca, 2021). Some evidence suggests an association between red meat intake and the development of RA (Jin et al., 2021, Mosalmanzadeh et al., 2020, Romao and Fonseca, 2021). Overall, people with dietary behaviors close to the Western dietary pattern rich in refined grains, red and processed meat, sweets and hydrogenated fats are more likely to develop the disease due to the potential inflammatory effects of food components (Mosalmanzadeh et al., 2020, Deane et al., 2017).

However, a clear diet that would work preventively has not yet been found, as researches do not agree (such as the Mediterranean diet (Finckh et al., 2022, Romao and Fonseca, 2021), or the consumption of coffee and tea (Romao and Fonseca, 2021)), but the observance of a healthy and well-balanced diet rich in whole grain products, white meat, eggs, fruits, vegetables, and vegetable oils are recommended (Mosalmanzadeh et al., 2020, Romao and Fonseca, 2021). Likewise, consumption of omega-3 fatty acids and/or vitamin D reduced the incidence of autoimmune diseases in the elderly population (Hahn et al., 2021, Deane et al., 2017). Also, regular physical activity and moderate alcohol consumption are associated with a reduced risk of RA (Frazzei et al., 2022, Romao and Fonseca, 2021, Deane et al., 2017).

Obesity is associated with increased levels of pro-inflammatory cytokines (Arleevskaya et al., 2022) and thus with the development of RA (Frazzei et al., 2022, Finckh et al., 2022), especially in seropositive younger women suffering from abdominal obesity (Marchand et al., 2021). Also, the combination of obesity and smoking appears to synergistically increase the risk of RA (Frazzei et al., 2022, Deane et al., 2017).

Socio-economic background

A lower socioeconomic background is also a risk factor for RA disease (Frazzei et al., 2022), which can also be linked to lower educational attainment, when job opportunities are limited (Abdelsalam et al., 2023, Gomes et al., 2018, Kirkeskov and Bray, 2023). Working conditions for certain types of manual work are considered RA triggers, such as exposure to dust, fumes, chemicals and metals (predominance of male work – miner, construction worker, electrician, farmer or asphalt worker) (Murphy and Hutchinson, 2017).

Conclusion

The identification of genetic and environmental RA risk factors, along with blood biomarkers that predict disease progression, is important and may fuel future interest in developing preventive strategies before patients develop symptoms. It should be taken into account that the above-mentioned risk factors for the development of RA are often combined. Genetic predisposition, unhealthy diet, lack of physical activity, obesity, chronic stress as well as environmental exposures, low socioeconomic status are all interrelated, making it difficult to determine whether the causation found by studies is caused by one specific factor or a combination of them. As part of prevention, it is important to understand and investigate these factors in more detail (especially in people with a genetic predisposition), and if it is possible to reduce their risk and thus prevent the development of RA.

This work was supported by the Research and Development Support Agency under contract no. APVV-22-0587.

Authors:

M.Sc. Alexandra Husivargová Theofanidis Institute of Social and Behavioral Medicine, LF UPJŠ in Košice Department of Health Psychology, UMCG, University of Groningen, The Netherlands https://orcid.org/0000-0002-4639-4354

prof. MUDr. Kvetoslava Rimárová CSc. Institute of Public Health and Hygiene, LF UPJŠ in Košice https://orcid.org/0000-0003-4364-0553

Iveta Nagyová PhD, FABMR Institute of Social and Behavioral Medicine, LF UPJŠ in Košice https://orcid.org/0000-0002-9528-523

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