The three main entities that constitute AAV (GPA, EGPA, and MPA) share the same underlying pathology with the involvement of small/medium-sized vessels (arteries, arterioles, venules, and veins) without the typical vessel wall immune complex depositions that hallmark primary systemic vasculitis.⁵,⁶,⁷,⁸,⁹,¹⁴ GPA is a complex disease, and similar to most autoimmune diseases, the pathogenesis is multifactorial.⁷ Although the exact etiology remains elusive, it has a strong underlying autoimmune diathesis, which usually develops in genetically predisposed individuals where infectious, epigenetic, and environmental factors all contribute to the full spectrum of the pauci-immune necrotizing vasculitis that is universally observed with these disease entities.⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴ Although GPA, MPA, and to a lesser extent EGPA share fairly similar underlying etiopathogenetic events, orbital/periocular involvement in EGPA is rare and is even rarer in MPA, which rarely if ever involves the orbit or the upper respiratory tract.¹⁷

The pathogenesis of GPA passes through three phases. First is the acute phase, in which an aberrant autoimmune response is generated. This phase is championed by an initiating agent, which may be infectious. This is followed by an active injury phase mediated by ANCA antibodies directed against PR3 and MPO autoantigens, the expression of which on the surface of neutrophils appears to be genetically determined. The final phase is the response-to-injury phase, which predominantly involves monocytes, macrophages, and T lymphocytes.⁷

During the acute phase, several exogenous and endogenous agents can initiate a pathological ANCA response. Microbial agents such as Staphylococcus aureus as well as the Ross River virus have been implicated in the pathogenesis of AAV, which is probably attributable to the molecular mimicry between these microbial peptides and ANCA autoantigens particularly PR3.⁷,⁸ Drugs (propylthiouracil, cocaine, hydralazine, D-penicillamine, allopurinol, minocycline, and anti-TNF agents) and environmental factors (silica dust) can also trigger the development of GPA.⁵,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴

During the active injury phase, neutrophils appear to be the major effector cells in the pathogenesis of GPA. Normally,
resting neutrophils have ANCA autoantigens (MPO and PR3) sequestered within the cell.⁷ Upon exposure to an infectious or an exogenous agent, dendritic cells present the antigen to naïve T cells, which initiates a complex cascade of events that ultimately results in the priming of neutrophils, with the release of MPO and PR3 onto the surface of neutrophils as well as in the microenvironment around the cells.¹⁴

One of the quintessential steps in the pathogenesis of ANCA vasculitis is antigen presentation, and it is at this point in the pathogenetic cascade of AAV where genetic predisposition probably comes into play.¹⁴ The genetic basis of GPA is undisputed and many of the genes described so far encode proteins that are involved in the immune response.⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ Genome-wide association studies have repeatedly provided evidence that the most convincing or strongest genetic association has been with major histocompatibility complex class II (MHC II) genes.¹⁴,¹⁶ Susceptibility to GPA, therefore, is strongly associated with the expression of specific MHC II genotypes that are apt to present MPO or PR3 antigens to the immune system, which results in the production of ANCA.¹⁴ Therefore, specific MHC II genetic traits correlate with certain types of ANCA autoantigens, which results in their increased membrane expression. Antibodies thus bind to the specific autoantigen presented at the surface of the cell, which ultimately directs the clinicopathologic expression of the disease.⁵,⁷,¹⁴

Although new associations between GPA and genetic polymorphisms continue to be reported and updated frequently in the literature, the HLA-DP locus has the strongest association with GPA.¹⁹ Other genetic loci associated with GPA include SERPINA1 and PRTN3.¹¹,¹⁴ Animal models, clinical observations, and histopathologic studies have repeatedly demonstrated the central role played by ANCA antibodies in the pathogenesis of the disease.⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵ The two major target antigens for ANCA autoantibodies in patients with AAV vasculitis are MPO and PR3, which are located within the granules of neutrophils, in the lysosomes of monocytes, and on the surface of neutrophils.¹³ GPA is hallmarked by ANCA autoantibodies, which are more commonly directed against the PR3 and less commonly against MPO.¹¹ However, MPA is more commonly associated with MPO-ANCA than with PR3-ANCA.¹¹,¹² Overall, about 10% of AAV patients are ANCA negative, a feature which is more commonly encountered in EGPA, where almost 30% to 50% of patients are ANCA negative, but the pathologic manifestations in ANCA-negative patients are similar to those of ANCA-positive patients.⁷,¹¹,¹²,²⁰

This binding of autoantibodies to primed neutrophils results in excessive activation of neutrophils.⁷,¹⁴ Those activated neutrophils adhere to and penetrate vessel walls, and later undergo leukocytoclasis, a process whereby neutrophils undergo degeneration (karyorrhexis), with the formation of nuclear dust, subsequently releasing inflammatory cytokines, reactive oxygen species, and lytic enzymes in the extracellular milieu, and then the neutrophils finally disappear, to be replaced by mononuclear leukocytes including macrophages, monocytes, as well as T lymphocytes in later phases of the disease.⁷,⁸,⁹,¹⁰,¹¹,¹²,¹⁴,¹⁵,¹⁶,²¹ Furthermore, during the acute phase, the excessive activation of neutrophils by ANCAs induces the formation of neutrophil extracellular traps (NETs). The formation of NETs, which are a normal element of innate immunity, is a remarkable process by which neutrophils eject nuclear DNA impregnated with lethal antimicrobial agents into the extracellular space, creating what looks like a net trapping potential pathogens. NETs are subsequently eliminated later by an enzyme called the DNase I enzyme.⁷,¹⁴ Although this is a normal physiologic process, if it exists in excessive amounts or if the NETs are insufficiently eliminated by the enzyme, NET formation in itself becomes harmful to small vessels. Interestingly, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs by impairing DNase I activity; therefore, a NET-ANCA vicious cycle is accomplished, and further ANCA production is established, which contributes further to the pathogenesis of AAV.⁷,¹⁴ Because ANCAs also bind to PR3 and MPO antigens on endothelial cells and other tissue sites of injury, ultimately, this entire process results not only in the apoptosis and destruction of neutrophils but also in the destruction of vessel walls and involved tissues.⁵,⁷

There is an ongoing debate as to whether GPA and MPA represent distinct diseases or are part of a single disease spectrum, but the consensus is that they are distinct autoimmune syndromes.¹¹,¹⁶ The abovementioned genetic data do support the notion that GPA does appear to be genetically distinct from MPO and other AAV-associated diseases. Confusingly, newer genetic data strongly suggest that the HLA genomic signature of AAV vasculitides is strongly associated with ANCA specificity (PR3-ANCA vs MPO-ANCA) rather than the clinical manifestations (GPA, MPA, or EGP).¹⁴,¹⁶ Whether this means a new classification of AAV is on the horizon remains to be determined.

GPA has an annual incidence of 5 to 10 per million per year and a prevalence of 3/100,000.²² The disease is more common in middle-aged white males older than 50 years, but it is rarely reported in children and the elderly.¹⁷,²³,²⁴ Ocular/adnexal involvement is usually unilateral, but it may be bilateral in 14% to 58% of patients.²⁵,²⁶,²⁷ Ocular and adnexal disease is usually observed in up to 87% of generalized GPA patients at some point during their lifetime and may be the presenting feature of the disease in up to 16% of patients.²⁸,²⁹