tory signals) have been found to express PR3 and MPO, thus perpetuating the presentation of self-antigens and production of ANCAs, and could trigger or increase in ammatory responses in the endothelia, especially in the kidneys [44]. Changes, maturation (such a glycosylation level), and epigenetic changes in PR3-ANCA production and/or conformation can also lead to increased pathogenicity of the autoantibodies [40, 45]. GPA has been associated with excess production of certain soluble factors of stimulation and proliferation of B lymphocytes (B-cell-­ activating factor (BAFF) 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 costimulatory molecules, including increased membrane expression of CTLA4, can lead to rupture of immune tolerance mechanisms.

The binding of ANCAs results in activation of the alternative complement pathway and production of reactive oxygen species by neutrophils, all of which lead to endothelial injury. Both the depletion of neutrophils and the blockade of the complement pathway prevent the development of MPO-­ ANCA-­induced vasculitis in experimental models [46, 47].

Granuloma formation, an important histological characteristic of GPA, involves lymphocyte subpopulations, with not only a preferential cytokine secretion profle of TH1 lymphocytes (interferon-gamma) but also other complex cytokine imbalances, cell populations, or immune pathways of a more recent discovery, such as TH17 lymphocytes, a source of IL-17, dendritic, or natural killer cells.

Finally, functional abnormalities of endothelial cells have been described, and serum autoantibodies against endothelial cells have been found in some patients.

Clinical Manifestations

The main clinical manifestations of GPAs and their frequencies are displayed in Table 8.2. 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. Disease damage and possible complications of treatment are discussed in another section of this chapter.

Constitutional Symptoms

Constitutional and musculoskeletal symptoms are common and include asthenia, fever, weight loss, diffuse myalgias,

arthralgias, or sometimes genuine in ammatory arthritis with reported cases of oligoor polyarthritis.

Ear, Nose, and Throat (ENT) Manifestations

More than two-thirds of patients have ear, nose, and throat manifestations, which often represent the frst symptoms of the disease. When isolated, such symptoms can result in diagnostic delays. Persistent nasal obstruction, nasal or sinus pain, sinusitis, rhinitis, recurrent epistaxis and/or nasal crusting, or serous otitis media and/or hypoacousia should alert physicians to the possibility of GPA [5]. Hyposmia and/or hypogeusia are frequent.

The destruction of the nasal cartilage, which can lead to nasal septum perforation and/or saddle nose bridge deformity (Fig. 8.1), is highly suggestive, although not pathognomonic of GPA [48, 49]. The cartilage of the ears can also be affected (chondritis), as can the osteochondral tissues of the face and skull, with a rare occurrence of palate perforation or development of fstulas between the sinus and orbital cavities.

Another classic but rarer upper respiratory tract lesion (7–15% of patients) is subglottic stenosis, which is responsible for dysphonia and dyspnea with or without stridor and may require emergency procedures (dilatation with local injections of glucocorticoids or tracheostomy) [10, 49, 50]. Subglottic stenosis can be associated with endobronchial stenoses or can be isolated. It can occur in parallel with other manifestations or continuously progress despite control of disease elsewhere [51].

A computed tomography (CT) scan of the sinuses may show unilateral or bilateral sinusitis, osteochondral destruction and/or osteosclerosis (Fig. 8.2), otitis media, and/or mastoiditis. Granulomatous in ammatory tumors can also occur and can infltrate the sinuses, skull base, and/or orbits and be responsible for pain, proptosis, or contiguous pachymeningitis, which incur the risk of compression of the surrounding structures, such as the cranial (ophthalmoplegia) or optic nerves. CT scan fndings of subglottic stenosis should be studied in parallel with the results of a careful endoscopy (biopsies of subglottic stenosis are relatively sensitive but risky). Biopsies of nasal and/or sinus lesions can reveal granulomatous in ammation or vasculitis in about half of cases, when suffciently deep in and under the mucosa [52, 53]. In routine practice, nasal and sinus biopsies are often superfcial and rarely contribute to the diagnosis (abnormal in <25% of cases).

Fig. 8.1  Nasal deformity (bridge erosion) in a patient with granulomatosis with polyangiitis

Pulmonary Manifestations

The lungs are involved in 70–100% of patients, with clinical manifestations ranging from mild cough, dyspnea, chest pain, and intermittent hemoptoic expectoration to acute

Fig. 8.2  A sinus CT scan (horizontal) in a patient with granulomatosis with polyangiitis. Major destruction of the septum and midline cartilaginous structures, along with bilateral maxillary sinus osteosclerosis and atrophy

respiratory distress syndrome due to massive alveolar hemorrhage. In 6% of cases, lung involvement can remain asymptomatic, especially with lung nodules.

Lung nodules are among the most characteristic signs. A chest X-ray and a CT scan can show nodules in 40–66% of patients [54]; they are unilateral or bilateral, single or multiple (generally <10), measuring 0.5–10 cm in diameter, and excavated in half of cases (Figs. 8.3, 8.4, 8.5, and 8.6) [55]. A high-resolution chest CT should be obtained for all patients with respiratory symptoms because small nodules, early alveolar hemorrhage, and other early lesions may be missed on a chest X-ray. The differential diagnosis, including primary or metastatic tumors, and infections, especially tuberculosis or fungal infections, can be diffcult.

Alveolar hemorrhage (8–30% of patients) can occur at disease onset or later and can be associated with lung nodules [5]. It can be limited to a few bloody expectorations or become rapidly massive and be responsible for acute respiratory failure. However, sometimes, hemorrhage is suspected only on a chest CT scan (Figs. 8.6, 8.7, and 8.8; patchy, ground-glass opacities) and/or as unexplained anemia and then confrmed by bronchoalveolar lavage (persistently demonstrating hemorrhagic uid on sequential samples). Even when bleeding is obvious, bronchoalveolar lavage should be considered to rule out concurrent infection, even at disease onset.

Other pulmonary infltrates or lung consolidation (Fig. 8.5), unilateral or bilateral, may be observed in

Fig. 8.3  A chest CT scan (horizontal) in a patient with granulomatosis with polyangiitis. Large parenchymal excavated nodule (left lung)

Fig. 8.4  A chest CT scan (coronal) in a patient with granulomatosis with polyangiitis. Large parenchymal excavated nodules in both the lungs

Fig. 8.6  A chest CT scan (horizontal) in a patient with granulomatosis with polyangiitis. Parenchymal plain nodule (right lung) associated with multiple bilateral patchy opacities and diffuse posterior ground-­ glass opacities (probably corresponding to moderate alveolar hemorrhage)

Fig. 8.7  A chest CT scan (horizontal) in a patient with granulomatosis with polyangiitis. Diffuse bilateral ground-glass infltrate corresponding to massive alveolar hemorrhage

Fig. 8.5  A chest CT scan (horizontal) in a patient with granulomatosis with polyangiitis. Parenchymal plain nodule (left lung) associated with right lung posterior consolidation (and mild pleural effusion)

30–50% of patients and pleural effusion in 9–28% [5, 54]. Bronchial stenoses, usually on the main bronchia and/or frst branches, can occur and are often diffcult to manage, as mentioned previously (frequently associated with subglottic stenosis). These are best studied with a CT scan of the lungs (Fig. 8.9) and fberoptic bronchoscopy, which can reveal multifocal strictures and/or granulomatous endobronchial lesions. Spontaneous pneumothorax or pyopneumothorax are rare. Bronchiectasis is rarer in GPA than in MPO-ANCA-­associated vasculitis [56]. Similarly,