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.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are frequently occurring multifactorial diseases affecting joints. OA and RA may share not only tissue locations but also some molecular mechanisms. We compared different pathologies: anti-cyclic citrullinated peptide antibody (ACCP)-positive RA—the classical ‘antigen-driven’ pathology, starting in synovia with no signs of inflammatory process; ACCP-negative RA, starting with synovial inflammation triggered by nonspecific factors, which becomes a chronic process due to inherited innate immune peculiarities; and OA, starting with inadequate chondrocyte functioning and cartilage degradation with inflammation as a driving force. Notable coincidences in RA and OA development were revealed: shared mutations of 29 genes encoding molecules involved in immune-inflammatory processes and in ECM production; unidirectional association of OA and ACCP-negative RA with non-genetic triggers; and overactivation of signaling pathways with the same consequences for RA and OA. Innate and adaptive immune responses were involved in OA development. Similar to that observed in RA, lymphoid nodular aggregates were revealed in 30% of OA synovia. Myeloid, and especially pauci-immune and fibroid synovial pathotypes, are possible in OA. Indistinguishable from that in RA, pannuses were found in OA articular tissues. Thus, these coincidences may be evidence of evolution of some OA variants in RA.

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.

Background/Objectives: Patients with rheumatoid arthritis (RA) are prone to develop infections. Methods: Accordingly, 195 untreated early (e)RA patients and 398 healthy controls were selected from women in Tatarstan’s cohort to study infectious history in the anamnesis (four criteria) and in the previous year (16 criteria). Information about annual infections was collected face-to-face from year to year by a qualified rheumatologist/general practitioner and included the active use of information from medical records. Results: In the anamnesis, tuberculosis, and pneumonia, and in the previous year, respiratory tract infections, skin infections, and herpes simplex virus reactivation incidence were reported to be increased in eRA patients, as well as the event number and duration of acute and chronic tonsillitis. Moreover, more bacterial-suspected upper respiratory infections and urinary tract infections were retrieved in sporadic eRA patients as compared to familial eRA patients. An elevated immunization against CCP prevented respiratory tract infection in those with HSV exacerbation. Finally, associations were retrieved between infection (event number/delay) and RA indices: (i) chronic tonsillitis exacerbations with disease activity and health assessment (HAQ) in familial eRA; (ii) bacterial-suspected upper respiratory infections with the number of swollen and tender joints in sporadic eRA; and (iii) HSV exacerbation with inflammation in eRA patients with negative/low response against CCP. Here, we demonstrate the complex nature of the interplay of RA with specific infections. Conclusions: For the first time, differences in the patterns of annual trivial infections and their links with RA indices were found in cohorts of familial and sporadic cases of the disease. Additionally, for the first time, we identified a remarkable relationship between early RA and exacerbations of chronic tonsillitis, as well as tuberculosis in the patient’s history. Altogether, this study supports the existence of a complex interplay between infections and RA at onset driven by familial status and the presence of anti-CCP Ab at elevated levels.

BACKGROUND: Rheumatoid arthritis (RA) is a phenotypically heterogeneous disease. AIM: The study aimed to identify the role of triggers in the onset of RA and preclinical joint symptoms, as well as their association with clinical and laboratory parameters. METHODS: Data on potential disease triggers and preclinical joint symptoms were collected from patients with early RA (n = 461) and their relatives (n = 247). Moreover, 299 healthy participants (control group) were examined for past infections within the previous 6–12 months. Anxiety levels, number of childbirths, age at onset of menopause, and body mass index (BMI) were assessed. Additionally, the association of triggers with composite disease activity indices, morning stiffness duration, severity of functional joint impairment, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, anti-citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF) was assessed. Data were analyzed using the Mann–Whitney test, multiple regression analysis, and Spearman correlation. RESULTS: The most common triggers for RA and preclinical joint symptoms were menopause (17.6%, 11.7%), infections (13.4%, 15.8%), and psychological stress (15.2%, 18.2%). Preclinical joint symptoms were additionally provoked by physical exertion (19.8%). RA triggered by infections or menopause was associated with an increased frequency and duration of infections (p 0.001) and higher BMI (p = 0.019 and p = 0.024, respectively) compared with controls. A similar association was observed between preclinical joint symptoms triggered by infections and increased frequency and duration of infections (p 0.001). Additionally, joint symptoms triggered by physical exertion were associated with more frequent and prolonged infections compared with the control group (p = 0.015 and p = 0.016, respectively). ESR levels exhibited a heightened response when preclinical joint symptoms were associated with infections (p = 0.010), menopause (p = 0.033), or physical exertion (p = 0.020) in comparison with their response to psychological stress. The arthralgia score was highest when provoked by menopause compared with cases provoked by infection (p = 0.053) or childbirth (p = 0.012). Preclinical joint symptoms triggered by psychological stress were associated with a higher arthralgia score than those provoked by physical exertion (p = 0.002). In the preclinical group, ESR and CRP levels correlated with BMI (p = 0.005 and p = 0.028, respectively). In patients with RA, ACPA (p = 0.044) and RF (p = 0.009) concentrations were associated with personal anxiety levels. CONCLUSION: The influence of triggers on clinical and laboratory parameters is evident in preclinical RA. The highest arthralgia scores were observed in cases triggered by menopause or psychological stress. Joint symptoms associated with infections, menopause, or physical exertion were associated with higher ESR levels.