Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multifactorial disease influenced by genetic predisposition, environmental adjuvant factors, and immune system responses.
Let us focus our efforts on the environmental component. “Studies have shown that various environmental factors stimulate the body to activate neutrophils and expose their own antigens, resulting in the release of proteases and neutrophil extracellular traps, which damage vascular endothelial cells,” Wen-Man Zhao et al explained in a review article published in Frontiers in Immunology.
Several environmental factors have been described in the literature that contribute to the etiology and pathogenesis of AAV, including sustained exposure to silica and air pollutants, seasonal changes, and microbial infections, among others.
Silica, in particular, can be insidious as workers who process substances such as wood, grass, grain, cotton, sand, wool, soil, flint, and rock, among others, may become exposed to silica on a larger scale than the normal population.
Read more about AAV etiology
Environmental pollutants
Air pollution is a major public health concern. Air pollutants have a deleterious role in the health of the general population and may induce or exacerbate certain diseases.
The impact of air pollutants in the onset and development of AAV has been demonstrated in several studies. Exposure to carbon monoxide was positively correlated with AAV incidence. Moreover, heavy metal exposure—in particular exposure to cadmium, lead, and mercury—was associated with increased risk of granulomatosis with polyangiitis (GPA). Hydrocarbon exposure might also be a risk factor for both GPA and microscopic polyangiitis (MPA), but findings across different studies have been inconsistent.
There might be a link between AAV and exposure to environmental pollutants, organic solvents, and pesticides. This link might explain, at least in part, why the incidence of AAV is higher in rural areas than in cities in many European countries.
Some studies suggest that smoking is a risk factor for AAV, especially myeloperoxidase (MPO)-ANCA, and might increase disease recurrence. Conversely, other studies found that smoking may have a protective effect against AAV, possibly owing to the immunosuppressive effects of nicotine.
Silicon Dioxide
Exposure to silica seems to increase the risk of ANCA and to contribute increasing incidences of AAV. This has been supported by several studies showing that individuals working in agriculture, mills, drilling, painting, and textiles have a greater risk of developing AAV.
A retrospective study analyzing the incidence of AAV in 2 Australian health districts found higher levels of silica and solvent exposure in more than half of the study cohort (n=156).
Furthermore, surveys on post-earthquake disease prevalence also revealed an increase in the incidence of AAV, which has been attributed to increased atmospheric levels of silica resulting from the earthquake.
The molecular mechanisms underlying the association between silica exposure and AAV are unclear. Possible explanations are that silica exposure drives the activation of T cells and regulatory T cells, thereby leading to autoimmune dysfunction. Another theory is that silica induces the expression of MPO in the cell membrane of certain white blood cells, causing ANCA-related autoimmune responses.
Read more about AAV types
Seasonal Changes
Several studies have confirmed seasonality in AAV. However, there is no consensus about which season is more strongly associated with AAV onset and relapse.
Most studies have found peak incidence of AAV during winter, whereas at least 1 study has reported a higher incidence during summer, particularly in August. The incidence of kidney damage in patients with AAV also seems to be higher in winter. On the other hand, AAV relapse may be more frequent during autumn.
Two factors possibly related to a higher incidence of AAV during winter are the increased incidence of respiratory infections, which may trigger the occurrence of AAV, and the lower levels of vitamin D, which may cause immune dysfunction. However, these hypotheses need further confirmation.
Latitude
Geographical localization has a prominent role in AAV, according to epidemiological studies. The incidence of AAV varies greatly with latitude, which might be explained, at least in part, by differences in ultraviolet (UV) index.
Studies have shown that the risk of GPA is higher in the northern hemisphere, whereas the risk of MPA is higher in the southern hemisphere. Moreover, the incidence of GPA, eosinophilic GPA (EGPA), and leukocyte proteinase 3-ANCA was shown to vary with UV radiation intensity.
Microbial Infections
Microbial infection is a recognized risk factor in AAV. For instance, infections by the bacteria Staphylococcus aureus may trigger GPA disease activity, and chronic infection may increase the risk of recurrence. The detection rate of S. aureus in patients with GPA is significantly higher than that in healthy individuals.
Despite the strong association with GPA, current evidence does not support a role for S. aureus in the pathogenesis of MPA or EGPA.
In addition, several studies have suggested that imbalances in the respiratory tract microbiome may contribute to the incidence of AAV.
Associations with a variety of viruses have also been reported. These include parvovirus, hepatitis C virus (HCV), hepatitis B virus (HBV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV).
More than half (62.7%) of an Egyptian cohort (n=67) was found to be infected with HCV. The same study found a correlation between cytoplasmic ANCA and HCV antibody levels. Another study found that anti-HBc-positive patients with EGPA had a significantly higher risk of relapse.
Moreover, patients with AAV showed higher anti-EBV capsid antigen antibodies and anti-EBV early antigen antibodies than healthy individuals, and may develop anti-MPO antibodies following EBV infection.
Additional microorganisms, such as Aspergillus, Candida, Fusarium, Mycobacterium tuberculosis, Chlamydia pneumoniae, Tsukamurella pulmonis, and Helicobacter pylori may be associated with AAV, but studies are scarce.
Read more about AAV risk factors
Medication and Vaccination
There is a small group of AAV disorders known as drug-induced small vessel vasculitis. Several drugs have been implicated in such disorders, with particular emphasis on antithyroid drugs.
Propylthiouracil-induced AAV presents with similar clinical manifestations to those of primary AAV; however, it is less severe and prognosis is better as it tends to resolve after ceasing antithyroid therapy.
Treatment of drug-induced AAV is different from that of primary AAV. In patients with mild symptoms, immediate discontinuation of the causing drug can lead to disease remission, whereas patients with severe disease need a more aggressive approach to treatment, albeit immunosuppressive maintenance therapy is usually unnecessary.
Vaccines may also drive AAV. For instance, various cases have been associated with influenza and COVID-19 vaccines. In the case of COVID-19 vaccination, patients with existing AAV may experience recurrence. Conversely, there is no evidence supporting an association between influenza vaccination and AAV recurrence.
Reference
Zhao W-M, Wang Z-J, Shi R, et al. Environmental factors influencing the risk of ANCA-associated vasculitis. Front Immunol. 2022;13:991256. doi:10.3389/fimmu.2022.991256
Chung EYM, Risi D, Holt JL, et al. Retrospective study on the epidemiology of antineutrophil cytoplasmic autoantibodies-associated vasculitis in two Australian health districts. Intern Med J. 2022;52(4):605-613. doi:10.1111/imj.15098
