In this review, we explore systemization of knowledge about the triggering effects of non-genetic factors in pathogenic mechanisms that contribute to the development of rheumatoid arthritis (RA). Possible mechanisms involving environmental and individual factors in RA pathogenesis were analyzed, namely, infections, mental stress, sleep deprivation ecology, age, perinatal and gender factors, eating habits, obesity and smoking. The non-genetic factors modulate basic processes in the body with the impact of these factors being non-specific, but these common challenges may be decisive for advancement of the disease in the predisposed body at risk for RA. The provocation of this particular disease is associated with the presence of congenital loci minoris resistentia. The more frequent non-genetic factors form tangles of interdependent relationships and, thereby, several interdependent external factors hit one vulnerable basic process at once, either provoking or reinforcing each other. Understanding the specific mechanisms by which environmental and individual factors impact an individual under RA risk in the preclinical stages can contribute to early disease diagnosis and, if the factor is modifiable, might be useful for the prevention or delay of its development.

The characterization of risk and protective factors in complex diseases such as rheumatoid arthritis (RA) has evolved from epidemiological studies, which test association, to the use of Mendelian randomization approaches, which test direct relationships. Indeed, direct associations with the mucosal origin of RA are retrieved with periodontal disease (Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans predominantly), interstitial lung involvement, tobacco smoking and air pollutants. Next, factors directly associated with an acquired immune response include genetic factors (HLA DRB1, PTPN22), capacity to produce anti-modified protein antibodies (AMPA), and relatives with a history of autoimmune diseases. Finally, factors can be also classified according to their direct capacity to interfere with the IL-6/CRP/sIL-IL6R proinflammatory pathway as risk factor (body fat, cardiometabolic factors, type 2 diabetes, depressive syndrome) or either as protective factors by controlling of sIL-6R levels (higher education level, and intelligence). Although some co-founders have been characterized (e.g. vitamin D, physical activity, cancer) the direct association with sex-discrepancy, pregnancy, and infections among other factors remains to be better explored.

The clinical and immunological spectrum of acute and post-active COVID-19 syndrome overlaps with criteria used to characterize autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Indeed, following SARS-Cov2 infection, the innate immune response is altered with an initial delayed production of interferon type I (IFN–I), while the NF-kappa B and inflammasome pathways are activated. In lung and digestive tissues, an alternative and extrafollicular immune response against SARS-Cov2 takes place with, consequently, an altered humoral and memory T cell response leading to breakdown of tolerance with the emergence of autoantibodies. However, the risk of developing severe COVID-19 among SLE and RA patients did not exceed the general population except in those having pre-existing neutralizing autoantibodies against IFN-I. Treatment discontinuation rather than COVID-19 infection or vaccination increases the risk of developing flares. Last but not least, a limited number of case reports of individuals having developed SLE or RA following COVID-19 infection/vaccination have been reported. Altogether, the SARS-Cov2 pandemic represents an unique opportunity to investigate the dangerous interplay between the immune response against infectious agents and autoimmunity, and to better understand the triggering role of infection as a risk factor in autoimmune and chronic inflammatory disease development.

Introduction. Currently, there is evidence of a triggering role of environmental factors in developing rheumatoid arthritis (RA). The purpose of this work was to investigate the role of oxidative stress in provoking the preclinical stage of RAf in susceptible individuals and its possible relationship with the effects of ecotoxicants. Materials and methods. Examination of cases collecting biosamples was carried out during rheumatologic examination of the persons in the regional hospitals of 45 administrative districts of the Republic of Tatarstan (RT), Russia. Serum markers of oxidative stress were measured, namely levels of oxidized proteins, oxidized lipids, oxyguanine, and antibodies to oxidized LDL. The environmental parameters of residences of the persons included in the project were measured. Information was collected on the parameters of the environmental situation in the administrative districts of the Republic of Tatarstan in 2008-2018 (from publicly available reports of the Ministry of Ecology of the Republic of Tatarstan). Results. There was performed a comparison of the levels of oxidative markers in samples from individuals living in regions with the highest and lowest concentrations of certain atmosphere ecotoxicants, including carbon monoxide, hydrocarbons (volatile organic compounds (VOCs) free), particulate matter, VOCs, sulfur dioxide, and nitrogen oxide. The levels of oxidized proteins and oxidized LDL were significantly higher in residents of areas with the highest carbon monoxide and VOCs compared to residents of areas with the lowest content of these substances. The contribution of environmental indicators to the provocation of the anti-LDG antibody production in groups with genetic and preclinical RA stages was revealed to account for 40%. According to the results of multiple regression analysis, in individuals from the above groups and individuals at early RA stage, the levels of oxidized LDL and oxidized proteins depended on the effect of a combination of certain environmental factors. Limitations. In this article, we limited ourselves to the analysis of the RA association with air pollution indices. The study of other environmental factors (soil, water pollution, radiation levels) is ongoing. This will allow clarifying the specific mechanisms of the influence of the exposome on the development of the disease in total. In addition, the conclusions presented are speculative since the identified patterns were obtained by analyzing data in the limited data samples. Conclusion. Since environmental factors can be considered modifiable to a certain extent, the study of their role in the RA development and specific mechanisms of the disease triggered by these factors on persons at risk are of fundamental and applied importance.

Environmental factors are suspected of triggering rheumatoid arthritis (RA). One such factor is oxidative stress (OS), which is a step in ecotoxin detoxification and a damaging factor. The linkage of ecotoxin-triggered OS with clinical and laboratory RA indices in patients and individuals at the pre-RA stage was studied in patients with early (e) (n = 35) and advanced (a) stages of RA (n = 25) and individuals at pre-RA stages (FDR-First-Degree Relative(s), pre-RA, n = 72) in comparison with 52 healthy individuals without autoimmune and immunoinflammatory diseases in their family history (Controls). Ecotoxins within permissible concentration limits were associated with serum levels of OS markers in all cohorts, including Controls. Serum oxidized low-density lipoprotein (oxLDL) levels in pre-RA and eRA cohorts exceeded Control values. Significant differences were found in anti-oxLDL antibody correlations and OS markers. In pre-RA and both RA cohorts, a relationship was found with regards to serum antibodies to cyclic citrullinated peptide (ACCP) levels. Thus, ecotoxin-induced OS likely triggers pathogenic mechanisms at the pre-RA stage and RA onset.