Granulomatosis with Polyangiitis	8
Christian Pagnoux and Alexandra Villa-Forte

Granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis) is a systemic vasculitis characterized by necrotizing granulomatous in ammation predominantly affecting small-sized vessels, including the arterioles and arterial capillaries [1, 2]. It is rare, but the incidence has increased within the past few decades, at least in some northern countries, in part, possibly but not exclusively, because of better recognition [3, 4]. GPA primarily affects adults between 45 and 60 years of age but can also affect people of all ages. Upper and lower respiratory tract and/or kidney manifestations are the cardinal signs of the disease; several are quite suggestive, such as saddle nose deformity, subglottic stenosis, or lung nodular cavitations [5]. GPA is typically associated with anti-neutrophil cytoplasm antibodies (ANCAs) directed toward proteinase 3 (PR3-ANCAs) on ELISA. The etiology remains unknown, although knowledge of the major pathogenic mechanisms, however complex, has greatly improved in the past two decades [6].

The current modalities of treatment, when promptly initiated and properly applied, lead to remission in most patients, with a relatively low risk of side effects. Besides potent therapies used for more than 50 years, such as cyclophosphamide and glucocorticoids, others (namely, rituximab) have been found to be effective in inducing remission while also being less toxic, and additional therapeutic changes are expected to happen in the near future with the recent development of C5a and C5a receptor complement inhibitors. However, given the relapsing nature of the disease, maintenance immunosuppressive therapy needs to be prolonged, although its optimal duration remains unknown, and may

C. Pagnoux (*)

Vasculitis Clinic, Division of Rheumatology, Rebecca McDonald Centre for Arthritis and Autoimmune Diseases, Mount Sinai Hospital, University Health Network, Toronto, ON, Canada e-mail: [e-mail]

A. Villa-Forte

Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic,

Cleveland, OH, USA

vary according to several patient and disease characteristics [7, 8]. The search for newer therapies continues [9], as a few patients experience refractory disease, unrelenting relapses despite treatment, and/or particularly challenging manifestations such as subglottic stenosis or an orbital tumor, for which treatment can be particularly diffcult [10].

A Brief Historical Overview

The clinical picture of nasal cartilage destruction, consistent not only with the diagnosis of GPA but also with that of nasal natural-killer (NK)-cell lymphoma (previously known as lethal midline granuloma), was described in 1897 by McBride, an English otorhinolaryngologist. The subsequent published cases of GPA with histological evidence of vasculitis date back to 1931, when Klinger and Rössle at the Berlin Institute of Pathology reported two patients with “granulomatous polyarteritis” who died the following year after onset of the frst signs of the disease. In 1933, Rössle described two other patients with necrotizing vasculitis affecting the nasal cavities and upper airways. Then, in 1936 and 1939, Friedrich Wegener, a colleague of Klinger, reported three cases, all with rapidly fatal outcomes. In 1954, Churg, Fahey, and Godman defned the disease more precisely, clinically, and histologically and named it Wegener’s granulomatosis. Classifcation criteria were proposed in 1990 by theAmerican College of Rheumatology [11] and then by the Chapel Hill Consensus [2], which confrmed in 1994 the position of the disease within the necrotizing, systemic, small-sized vessel vasculitides (Table 8.1). In 2011, Wegener’s granulomatosis was offcially renamed GPA after delayed gathering of evidence that Wegener had some involvement in the Nazi Party during World War II and in a broader effort to eliminate medical eponyms [12]. International efforts since the 2012 Chapel Hill ANCA and vasculitis workshop include a revised nomenclature of the systemic vasculitides, incorporating the new name of GPA and further emphasizing that it is an ANCA-associated disease [13]. New classifcation criteria

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V. Cottin et al. (eds.), Orphan Lung Diseases, https://doi.org/10.1007/978-3-031-12950-6_8

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110	C. Pagnoux and A. Villa-Forte

Table 8.1  Classifcation criteria and defnition of granulomatosis with polyangiitis (Wegener’s granulomatosis), according to the American College of Rheumatology (1990) [11], 2021 [14], the nomenclature of the consensus conference held in Chapel Hill (NC) in 1993 [2] and revised in 2012 [13]

1990 American College of Rheumatology classifcation criteria for Wegener’s granulomatosis

For purposes of classifcation, a patient shall be said to have Wegener's granulomatosis if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specifcity of 92.0%

 1. Nasal or oral in ammation: Development of painful or painless oral ulcers or purulent or bloody nasal discharge

 2. Abnormal chest radiograph: Chest radiograph showing the presence of nodules, fxed infltrates, or cavities

 3. Urinary sediment: Microhematuria (>5 red blood cells per high power feld) or red cell casts in urine sediment

 4. Granulomatous in ammation on biopsy: Histologic changes showing granulomatous in ammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)

2021 American College of Rheumatology classifcation criteria for granulomatosis with polyangiitis

The classifcation criteria for granulomatosis with polyangiitis can be considered only in patients in whom: (1) diagnosis of smallor medium-sized vessel vasculitis has been made and (2) all alternate diagnoses have been excluded, and are:

Clinical criteria	Nasal involvement: bloody discharge, ulcers crusting, congestion, blockage or septa defect/perforation	+3
	Cartilaginous involvement (in ammation of ear or nose cartilage, hoarse voice or stridor,	+2
	endobronchial involvement, saddle nose deformity)
	Conductive or sensorineural hearing loss	+1
Laboratory, imaging,	Cytoplasmic antineutrophil cytoplasmic antibody (cANCA) or antiproteinase 3 ANCA (PR3-ANCA)
and biopsy criteria	positivity
	Pulmonary nodules, mass or cavitation on chest imaging
	Granuloma, extravascular granulomatous in ammation, or giant cells on biopsy
	In ammation, consolidation or effusion of the nasal/paranasal sinuses, or mastoiditis on imaging
	Pauci-immune glomerulonephritis on biopsy
	Perinuclear ANCA (pANCA) or antimyeloperoxidase ANCA (MPO-ANCA) positivity	−1 (subtract)
	Blood eosinophil count ≥1 × 109/L	−4 (subtract)

A cumulative, sum score of ≥5 is needed for classifcation of granulomatosis with polyangiitis. The sensitivity of these criteria was 93% (95% CI; 87–96%) and specifcity 94% (95% CI; 89–97%)

Defnition of Wegener’s granulomatosis in the nomenclature of systemic vasculitis adopted in 1994 by the Chapel Hill consensus conference

Large vessel vasculitis: Giant cell (temporal) arteritis; Takayasu’s arteritis

Medium-sized vessel vasculitis: Polyarteritis nodosa; Kawasaki’s disease

Small vessel vasculitis:

 Wegener’s granulomatosisa

 Granulomatous in ammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels, e.g., capillaries, venules, arterioles, and arteries

 Necrotizing glomerulonephritis is common

 Churg-Strauss syndromea

 Microscopic polyangiitisa

 Henoch-Schönlein purpura

 Cryoglobulinemic vasculitis

 Cutaneous leukocytoclastic angiitis

   Small artery refers to distal arterial radicals that connect with arterioles. Small vessels include small arteries, arterioles, venules, and capillaries

Defnition of granulomatosis with polyangiitis (Wegener’s) in the 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides

Large vessel vasculitis: Giant-cell arteritis; Takayasu arteritis

Medium vessel vasculitis: Polyarteritis nodosa; Kawasaki disease

Small vessel vasculitis:

 ANCA-associated vasculitis

 Microscopic polyangiitis

 Granulomatosis with polyangiitis (Wegener’s)

 Necrotizing granulomatous in ammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulonephritis is common

   Eosinophilic granulomatosis with polyangiitis (Churg Strauss)

 Immune complex vasculitis

   Anti-GBM disease cryoglobulinemic

   Vasculitis IgA vasculitis (Henoch-Schönlein)

   Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)

Variable vessel vasculitis: Cogan’s syndrome; Behçet’s disease

Single organ vasculitis

Vasculitis associated with systemic disease

Vasculitis associated with probable etiology

  Large vessels are the aorta and its major branches and the analogous veins. Medium vessels are the main visceral arteries and veins and their initial branches. Small vessels are intra-parenchymal arteries, arterioles, capillaries, venules, and veins

a These vasculitides are associated with ANCA

8  Granulomatosis with Polyangiitis	111

have been conjointly developed by the American College of Rheumatology and the European League Against Rheumatism (EULAR) and have been offcially published in 2021, which reinforces the role of PR3-ANCAs in the defnition of GPA [14].

Epidemiology

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 ffth decade (Table 8.2), but young children and older adults can also be affected. Most patients (93–98%) are white (Caucasian and Hispanics). The estimated annual incidence is 2–30 cases per million people, and the prevalence is 20–260 cases per million people [3, 4, 15]. A north-south gradient is suggested, at least in Europe, because the reported annual incidence is twice higher in Norway, for example, than in Spain (15 vs. 4.9 per million inhabitants) [16]. Conversely, PR3-ANCA + GPA is rare in Japan, where anti-myeloperox- idase (MPO-ANCA) + disease (mostly of the microscopic polyangiitis-type) represents most cases of ANCA vasculitis. Notably, the incidence of the disease also seems to have increased within the past few decades, according to several European studies, although some of these changes could be related, at least in part, to a better understanding and awareness of the disease and thus more frequent and earlier diagnoses [4, 15, 17]. A British study also suggested peaks of incidence every 8–10 years (17.4 per year per million people during peaks vs. only 4.53 per year per million people during no peaks) [16]. Seasonal variations in GPA incidence have been reported but with con icting results [18].

The existence of these potential geographic and temporal variations in GPA incidence suggests a potential pathogenic, or at least a participating, role of environmental (allergic, chemical, and/or infectious) and/or genetic factors in the development of the disease. The association between 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 [19]. 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 [20]. Finally, an inverse relation between the intensity of sun exposure, specifcally ultraviolet rays, and GPA prevalence suggests a possible link to vitamin D defciency, as has been suggested in many other autoimmune diseases [21].

GPA is not an inherited or genetic disease. Familial forms are extremely rare, with a small and insignifcant relative risk of GPA among frst-degree relatives of GPA patients (hazard ratio (HR) 1.56; 95% confdence interval (95% CI) 0.35–6.90), as compared with the general population. However, frst-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) [22]. Personal (and probably also familial) history of autoimmune thyroiditis has been found more frequently in GPA patients than in the general population (13% of GPA patients) [23]. Some genetic predisposition is thus likely, although not enough to explain or trigger the disease by themselves. Several international teams have conducted studies on

Table 8.2  Characteristics of patients with granulomatosis with polyangiitis and frequency (percent), according to the main studies published between 1958 and 2020

Characteristic		Range	Mean
Mean age at diagnosis (years)		14–58	48
Clinical presentations/organ involvement (%)
Ear, nose, and throat		56–99	70
	Kidney	18–100	58
	Lung	40–100	57
	Arthralgias	15–77	52
	Fever	17–72	45
	Eye	2–61	34
	Skin	12–50	29
	Peripheral nervous system	7–68	20
	Heart	0–30	13
	Gastrointestinal	0–42	12
	Central nervous system	0–13	8

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112	C. Pagnoux and A. Villa-Forte

genome-wide associations with GPA. Many, and sometimes variable, genetic associations have been reported, with the two most reproducible being those for molecules of major histocompatibility complex (MHC) HLADPB1*0401 (odds ratio (OR) 3.38 for patients with ANCAs) and, to a lesser degree, allele defciency of alpha-1 antitrypsin (serpin A1; PI*Z alleles in 5–27% of GPA patients, PI*S alleles in 11.58%, homozygosity for defciency ZZ, SS, or SZ having more severe forms) [24]. 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 Fc-alpha receptors, intracellular tyrosine phosphatase PTPN22 (620W allele), transforming growth factor beta-1, interleukin-10 (IL-10) promoter, CTLA-4, or CD226 (Gly307Ser) polymorphism allele [24, 25]. GPA has been associated with other MHC molecules, including DR2 and DR4 alleles HLA-DRB1*04, B8, DR1DQw1, B50-DR9, and DR9 in Japanese patients. Conversely, the DR13-DR6 phenotype was found to be less frequent among Norwegians with GPA than among healthy subjects.

More importantly, perhaps, the most recent studies have shown that genetic susceptibility is more linked to the ANCA type (PR3-ANCAs with HLA-DP and the genes encoding α1-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) versus MPO-ANCAs with HLA-DQ) than to the clinical phenotype (GPA versus microscopic polyangiitis) [26]. Whether the classifcation of ANCA-associated vasculitides should be modifed according to these results remains under debate [8, 27].

Pathogenesis

GPA is considered an autoimmune in ammatory disease. Defning its pathogenic mechanisms has advanced enormously within the past three decades, especially since the discovery of ANCAs in 1985 [17]. However, the primum movens of the disease remain(s) to be identifed [6, 28].

The hypothesis of an infectious agent, such as Staphylococcus 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 as shown in one study, possibly by maintaining a local in ammatory immune response within the nasal mucosa [29]. A selective cross-reactivity of T cells toward 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 complementary protein idiotype–anti-idiotype mechanism [30]. The S. aureus infection found in GPA patients is not from a particular strain and does not produce specifc toxins or lead to a specifc T-cell repertoire selection through superantigenic mechanisms [31]. Other organisms could have also been involved, such as Staphylococcus pseudintermedius or Corynebacterium tuberculostearicum, based on recent nasal microbiome studies [32–36].

Irrespective of the signal for their synthesis, PR3-ANCAs are detected in more than 80% of patients with generalized GPA. However, their pathogenic role is less well-documented than that of MPO-ANCAs (most characteristic of microscopic polyangiitis). Animal models of vasculitis associated with PR3-ANCAs remain less convincing and require many preliminary alterations of the immune system of the animal model as compared with those associated with MPO-­ ANCAs. In the mouse model of Pfster et al., vasculitis induced by transfer of PR3-ANCAs remained localized to the mouse footpads, was not granulomatous, and required prior sensitization with subcutaneous injections of tumor necrosis factor-α (TNF-α) [37]. In the BALB/c murine model of Pendergraft et al., mice did not develop overt vasculitis [30]. Two other subsequent murine models of PR3-ANCA-­ associated vasculitis have been developed and are more convincing but require specifc 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) [38, 39]. Specifc alterations and “maturation” may be necessary for PR3-ANCAs to become pathogenic, including the selection of higher-affnity ANCAs in the nasal mucosa granulomas or modulation of their sialylation levels [40]. Whereas results from recent studies of therapies targeting B cells (i.e., rituximab) have seemed to provide indirect evidence for the potential pathogenic role of PR3-ANCAs, these biological agents may (also) act through other more complex pathways [41–43].

Other factors or mechanisms involved in GPA can favor or enhance the PR3 and PR3-ANCA interaction and thereby the immune response. Besides the frequent functional and/or genetic defcit in 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 (NETs, the cellular activation debris produced in response to in amma-