GPA affects both genders equally. Only a few studies, mostly those of localized/limited GPA, have suggested a relatively greater frequency in women. The median age at diagnosis is in the fifth decade (Table 9.2), but young children and older adults can be affected. Most patients (93–98 %) are white (Caucasian and Hispanics). The estimated annual incidence is 2–12 cases per million population and the prevalence 23–160 cases per million population [3]. A north-south gradient is suggested, at least in Europe, because the reported annual incidence is twice as high in Norway, for example, than in Spain (10.6 vs. 4.9 per million inhabitants) [11]. Conversely, antiPR3+ GPA is rare in Japan, where anti-myeloperoxidase (antiMPO) + disease (mostly microscopic polyangiitis-type) represents most cases of ANCA vasculitis. Notably, the incidence of the disease seems also to have increased within the past decades, according to several European studies, although whether these changes could be related, at least in part, to a better understanding of the disease and thus lead to more frequent and earlier diagnosis, especially since the discovery of ANCA in 1985, remains controversial [12]. A recent British study suggested peaks of incidence every 8–10 years (17.4 per year per million population during peaks vs. only 4.53 per year per million population not during peaks) [11]. Seasonal variations in GPA incidence have been reported, but with conflicting results.

The existence of these potential geographic and temporal variations in GPA incidence suggest a potential pathogenic, or at least participating, role of environment (allergic, chemical and/or infectious) and/or genetic factors in the development of the disease. The association of GPA and silica exposure, industrial pollutants such as cadmium, mercury derivatives or other heavy metals such as lead, volatile hydrocarbons or organic solvents has been reported. Other studies have suggested links between GPA and the inhalation of dust, especially during livestock activities [13]. However, GPA does not seem more frequent in rural areas, and exposure to such environmental agents is found in no more than 10 % of all GPA patients [14]. Finally, an inverse relation between the intensity of sun exposure, specifically ultraviolet rays, and GPA prevalence suggests a possible link with vitamin D deficiency, as has been suggested in many other autoimmune diseases [15].

GPA is not an inherited or genetic disease. Familial forms are extremely rare, with a small and insignificant relative risk of GPA among first-degree relatives of GPA patients (hazard ratio [HR] 1.56, 95 % confidence interval [95 % CI] 0.35–6.90), as compared with the general population. However, first-degree relatives may be more likely to develop other autoimmune diseases (HR 1.32, 1.18–1.49), including multiple sclerosis (HR 1.92), Sjögren’s syndrome (HR 2.00) or rheumatoid arthritis (HR 1.54) [16]. Personal (and probably also familial) history of autoimmune thyroiditis has been found more frequently in GPA than in the general population (13 % of GPA patients) [17]. Factors related to genetic predisposition are thus likely, although not enough to explain or trigger the disease by themselves. Several international teams are conducting studies on genome-wide associations with GPA.Many variable genetic associations have indeed been reported, the two most reproducible being those for molecules of major histocompatibility complex (MHC) HLA–DPB1*0401 (odds ratio [OR] 3.38 for patients with ANCA) and, to a lesser degree, allele deficiency of alpha-1 antitrypsin (serpin A1; PI*Z alleles in 5–27 % of GPA patients, PI*S alleles in 11.58 %, homozygosity for deficiency ZZ, SS or SZ having more severe forms) [18]. Many other genetic associations have been reported, including certain alleles of PR3-coding genes (−564 A/G), type IIa and IIIa/b Fc-gamma or -alpha receptors, intracellular tyrosine phosphatase PTPN22 (620 W allele), transforming growth factor-beta 1, interleukin-10 (IL-10) promoter, CTLA-4, or CD226 (Gly307Ser) polymorphism allele [18, 19]. GPA has been associated with other MHC molecules, including DR2 and DR4 allele HLA-DRB1*04, B8, DR1-DQw1, B50-DR9 and DR9 in Japanese patients. Conversely, the DR13-DR6 phenotype was found to be less frequent among Norwegians with GPA than healthy subjects.

More importantly perhaps, results of recent studies showed that genetic susceptibility was more linked with the ANCA type (antiPR3 with HLA–DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3); antiMPO with HLA–DQ) than with the clinical phenotype (GPA versus microscopic polyangiitis) [20]. Whether the classification of ANCA-associated vasculitides should be modified according to these results is now under debate.

GPA is considered an autoimmune inflammatory disease. Defining its pathogenic mechanisms has advanced enormously within the past three decades, especially since the discovery of ANCA in 1985 [12]. However, the primum movens of the disease remain(s) to be identified [5, 6].

The hypothesis of an infectious agent, such as Staphy-lococcus aureus, (over)activating the immune system has been repeatedly suggested. Chronic nasal carriage of S. aureus is considered a risk factor for relapse, as is observed in some but not all patients and shown in one study, possibly by maintaining a local inflammatory immune response within the nasal mucosa [21]. A selective cross-reactivity of T cells towards PR3 and S. aureus antigens has been suggested. The experimental model of Pendergraft et al. suggested that some antigenic motives of S. aureus have a molecular similarity with the protein synthesized from the complementary DNA segment coding for human PR3, which can trigger the production of antibodies against PR3 by a protein-complementary idiotype–anti-idiotype mechanism [22]. The S. aureus infection found in GPA patients is not from a particular strain and does not produce specific toxins or lead to a specific T-cell repertoire selection through superantigenic mechanisms [23]. Other organisms could also be involved. Recently, anti-lysosomal membrane protein 2 (antiLAMP2), another and newer type of ANCA, was detected by Kain and colleagues in more than 90 % of patients with ANCA-related (antiPR3 as well as antiMPO) glomerulonephritis [24]. This group further showed the LAMP-2 epitope with 100 % homology to the bacterial adhesin FimH located at the tip of type 1 fimbriae and crucial for attachment to host epithelia of Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. In addition, pauci-immune glomerulonephritis developed in rats immunized with FimH. However, those results have not been replicated and thus remain controvertial [25].

Whatever the signal for their synthesis, PR3-ANCA are detected in more than 80 % of patients with generalized GPA. However, their pathogenic role is less well documented than that of pANCA antiMPO (most characteristic of microscopic polyangiitis). Until recently, convincing animal models of vasculitis associated with antiPR3 ANCA were lacking as compared with those associated with antiMPO. In the mouse model of Pfister et al., vasculitis induced by transfer of antiPR3 ANCA remained localized to the mouse footpads, was not granulomatous and required prior sensitization with subcutaneous injections of tumor necrosis factor a (TNF-α) [26]. In the BALB/c murine model of Pendergraft et al., mice did not develop overt vasculitis [22]. More recently, two murine models of antiPR3 ANCA-associated vasculitis have been developed and are more convincing but require specific genetic backgrounds and prior subtle and complicated immune manipulations (including the humanization of the mouse immune system because of the lack of PR3 expression in murine neutrophils and low human and murine PR3 homology) [27, 28]. Specific alterations and “maturation” may be necessary for antiPR3 ANCA to become pathogenic, including the selection of higher-affinity ANCA in the nasal mucosa granulomas or modulation of their sialylation levels [29]. Although the pathogenicity of anti-PR3 ANCA remains difficult to demonstrate, results from recent studies of therapies targeting B cells (i.e., rituximab) provide indirect evidence for their potential role, unless these biologic agents act through other more complex pathways [30–32].

Other factors or mechanisms involved in GPA can favor or enhance the PR3-antiPR3 ANCA immune response or act independently. Besides the frequent functional and/or genetic deficit in α-1-antitrypsin, the physiological inhibitor of PR3, overexpression of PR3 on the neutrophil membrane, genetically determined, has also been reported. More recently, circulating microparticles derived from platelets, neutrophils or endothelial cells, as well as neutrophil extracellular traps (cellular activation debris produced in response to inflammatory signals), were found to express PR3 and MPO, thus perpetuating the presentation of self-antigens, and could trigger or increase inflammatory responses in endothelia, especially in kidneys [33, 34]. GPA has been associated with excess production of certain soluble factors of stimulation and proliferation of B lymphocytes (B-cell activating factor of the TNF family, also called B-lymphocyte stimulator). In parallel, functional abnormalities of the regulatory T lymphocytes CD4+ CD25+ FoxP3+ and abnormal expression of certain T-cell co-stimulatory molecules, including increased membrane expression of CTLA4, can lead to rupture of immune tolerance mechanisms.

The binding of ANCA results in activation of the alternative complement pathway and production of reactive oxygen species by neutrophils, all of which lead to endothelial injury (depletion of neutrophils or blockade of complement pathway both prevent the development of antiMPO-induced vasculitis in experimental models) [35, 36]. Granuloma formation, an important histologic characteristic of GPA, involves lymphocyte subpopulations, with a preferential cytokine secretion profile of TH1 lymphocytes (interferon-gamma), but also other complex cytokine imbalances, cell populations or immune pathways of more recent discovery, such as TH17 lymphocytes, a source of IL-17, dendritic or natural killer cells. Functional abnormalities of endothelial cells have been described, and serum autoantibodies against endothelial cells have been found in some patients.

The main clinical manifestations of the GPA and their frequencies are in Table 9.2. The most frequent target organs or systems are the upper and lower respiratory tracts and kidneys (necrotizing crescentic pauci-immune glomerulonephritis), but any organ can be affected. Complications of treatment and disease damage are discussed in another section of this chapter.