Box 8.1 Main Diagnostic Features of Granulomatosis with Polyangiitis (GPA)—There Is Presently No Ofcial and Validated Set of Diagnostic Criteria

Nonspecifc clinical and radiological features

•Constitutional symptoms: fever, arthralgias, myalgias, weight loss (in severe/generalized GPA)

•Skin purpuric lesions, sometimes necrotic (common to several medium and small vessel vasculitides)

•Mononeuritis multiplex (also common in several medium and small vessel vasculitides)

More suggestive clinical and radiological features

•Signs of glomerulonephritis: microscopic hematuria (>5 red blood cells per high power feld) with proteinuria and red cell casts in urine sediments (also in other small vessel vasculitides), and then renal function impairment

•Ear, nose, and throat manifestations: nasal or oral ulcerations, recurrent serous otitis media, painful eroding sinusitis, purulent or bloody nasal discharge with nasal crusting, septum perforation and/or saddle nose deformity, subglottic stenosis

•Lung manifestations: alveolar hemorrhage (also in some other small vessel vasculitides), parenchymal nodules or cavities, bronchial stenosis

•Other “granulomatous-type” lesions: pachymeningitis, orbital (pseudo-)tumor, dorsal prevertebral lesions

•Eye lesions: scleritis, dacryocystitis or dacryoadenitis, retinal involvement

Laboratory investigations to support the diagnosis

•Detection of serum ANCAs (mainly, but not always and not exclusively, PR3-ANCAs; 50–75% of the patients with limited GPA, 80–90% of those with severe/generalized GPA)

•Evidence of granulomatous in ammation within the wall of a small artery or arteriole on biopsy of an affected organ/ tissue with/without fbrinoid necrosis (the diagnostic yield varies depending on which organ is biopsied—highest for open-lung biopsies, lowest for nasal mucosa biopsies)

Laboratory Investigations

Biology

Nonspecifc in ammatory syndrome is common at diagnosis and during disease ares, with an increased neutrophil count, normochromic normocytic anemia (50–73% of patients, usually worse in patients with alveolar hemorrhage), and thrombocytosis (30–65%) [5]. Erythrocyte sedimentation rate in the frst hour and C-reactive protein level are increased in almost every patient with active disease [103].

Transient and moderate eosinophilia can occur, in less than 12% of patients and rarely above 2000/mm3, sometimes with a concomitant increase in the serum IgE level. High levels of IgE and/or atypical fndings, including asthma, should suggest eosinophilic granulomatosis with polyangiitis. IgG4 levels are sometimes elevated, raising the question of possi-

ble overlapping presentations [59, 60]. Moderate lymphopenia, 700–750/mm3, is common at diagnosis (and during active disease) but can also result from and/or be induced by glucocorticoid therapy [104].

Routine laboratory tests should systematically be a part of the initial workup and monitoring during the disease course. Analysis of fresh urine sediments is important for all patients for the detection of red blood cell casts, which are more suggestive of a glomerular disease than a tubular or interstitial condition.

Immunology

The 2017 revised international consensus statement recommends high-quality antigen-specifc immunoassays such as enzyme-linked immunosorbent assay (ELISA), capture ELISA, or multiplex microbead immunoassay as the initial screening test for PR3-ANCAs and MPO-ANCAs [105]. This position is now widely adopted by most groups [106]. In the case of a negative result with a high clinical suspicion, a testing through indirect immuno uorescence (IIF) can still be considered, which demonstrates variable performance across laboratories and detection methods. Patients with PR3-ANCAs would most often be positive in IIF with a cytoplasmic (C-ANCA) uorescence pattern.

As already stated, the frequency of ANCA detection is lower in patients with limited GPA (50–75%) than generalized GPA (80–90%). A negative ANCA thus does not rule out ANCA-associated vasculitis (AAV) in the appropriate clinical context of active disease [23]. Conversely, ANCAs can also be present in other conditions, some of which can mimic vasculitis, such as endocarditis, tuberculosis, or amebiasis. Few patients with microscopic polyangiitis (or, exceptionally, with eosinophilic granulomatosis with polyangiitis) can have PR3-ANCAs rather than MPO-ANCAs, and the diagnosis of GPA may be diffcult to establish with certainty. Use of cocaine, through any route and especially if cut with levamisole, can cause vasculitis-like necrotic skin lesions and nasal septum perforation similar to that seen in GPA and can be associated with various ELISA results (MPO-ANCAs or PR3-ANCAs, both, or ANCAs directed toward different antigens such as elastase) [107]. Patients with associated in ammatory bowel disease, chronic liver diseases (chronic hepatitis C or autoimmune liver diseases), or certain infections (endocarditis, fungal infections, tuberculosis) can also show low and, usually, transient titers of ANCAs (and/or other autoantibodies).

In addition, patients with high ANCA titers can test positive, usually transiently, for other autoantibodies. The detection of rheumatoid factor has been reported in some series, in up to 70% of patients, but is not specifc and is usually seen at low titers, and anti-cyclic citrullinated peptide test results are usually negative. Patients with alveolar hemorrhage and/or renal

involvement should undergo systematic testing for anti-­ glomerular basement membrane (GBM) antibodies. An association of the two antibodies (ANCA and anti-GBM) can occur in a few (<5%) patients with pulmonary renal syndrome, who have worse global and renal prognosis than do patients with only one of the two autoantibodies, and require a specifc treatment approach (including plasma exchange therapy) [108].

Radiology, Endoscopy, and Other

Nonbiological Investigations

Ideally, imaging of the chest must always be performed with a CT scan. Other radiological investigations (CT scan of sinuses, MRI or MR angiography of the head, ultrasonography, or CT scan of the abdomen and pelvis) should be performed depending on clinical fndings. Abdominal angiography (conventional or CT) is not part of the usual diagnostic evaluation (as opposed to polyarteritis nodosa). If performed, physicians should not forget that microaneurysms of the renal, splenic, and/or liver arteries, although primarily characteristic of polyarteritis nodosa, can occasionally be seen in GPA or other small-sized vessel vasculitides [109].

Nasal fbroscopy can be useful in patients with ear, nose, or throat manifestations but is cautioned in patients with subglottic stenosis (because of the risk of spasm or post-trau- matic in ammatory edema), to assess the extent of lesions and/or to perform biopsies, although sensitivity may be low. Bronchial endoscopy with bronchoalveolar lavage can help support a diagnosis of alveolar hemorrhage, identify and assess in ammatory bronchial stenosis or lesions, and, perhaps more importantly, exclude infections (or neoplasia). When the patient’s condition allows for it, transbronchial biopsies can be performed; however, sensitivity is not as good as with open-lung biopsies [5, 53]. In the presence of digestive symptoms, upper endoscopy and/or colonoscopy may be needed. These can reveal ulcers, especially in the ileocolon or anorectal junction, sometimes with a similar appearance as in Crohn’s disease, and also in the stomach or esophagus. A gastrointestinal biopsy incurs some risks (i.e., perforation) in these patients, and the sensitivity is low.

Patients with peripheral neurological symptoms, especially those as subtle and nonspecifc as tingling in the fngers or feet, should undergo electromyography with a nerve conduction study to confrm or exclude peripheral neuropathy. Subclinical nerve involvement can been seen and may dictate a more aggressive treatment [66]. Electromyography results may also guide nerve or muscle and nerve biopsy, when considered. Many patients have transmission (up to 33% of patients) and/or neurosensory perception (47%) hypoacousia, which can ideally be quantifed on audiography.

Pathology

GPA affects small-sized vessels, capillaries, and, sometimes, venules, less commonly medium-sized vessels, and rarely large-sized ones (the aorta). Therefore, biopsies of the affected organs can help support the diagnosis and reveal (1) vessel wall infltration, mainly by neutrophils and lymphocytes (sometimes also with some eosinophils), (2) fbrinoid necrosis, and/or (3) poorly formed granulomas, sometimes with palisading organization and/or giant cells. The coexistence of these three histological aspects may be considered to be highly suggestive of the diagnosis, but they are not always present in the same sample. The decision to seek a histological diagnosis must be balanced with the risk of the biopsy itself, especially when the clinical features suggestive of GPA and PR3-ANCAs are positive.

Biopsies of skin lesions are easy to perform and can reveal nonspecifc leukocytoclastic vasculitis. Some other aspects are a little bit more (but not totally) specifc, such as the presence of extravascular poorly formed granulomas, vasculitis with granulomas, or sterile abscesses with granulomas. Nasal and sinus mucosa biopsies are also relatively simple to perform but should be deep enough, and multiple samples should be obtained because of low sensitivity (less than half of the sinus biopsies and only 20% of the nasal biopsies contribute to the diagnosis [52]).

Tracheal biopsies, in patients with subglottic stenosis, can be associated with an increased risk, are often superfcial, and are therefore not highly sensitive or helpful in clinical practice (<18% show some histological features). Biopsies of lung nodules usually require surgical procedures, but they can show vasculitis in >60% of cases. In alveolar hemorrhage, the usual aspect on histology is capillaritis. In the study by Duna et al., transbronchial biopsies revealed ­vasculitis in 7% of cases and evidence of both vasculitis and granulomas in 5% [110]. However, open-lung biopsies showed vasculitis and necrosis in 89% of cases, granulomas and necrosis in 90%, and all three features in 91% (Fig. 8.12). ENT and lung biopsies may also be extremely helpful to rule out infections, especially fungal infections (using different and specifc staining methods).

A renal biopsy (in patients with renal involvement) typically shows pauci-immune glomerulonephritis (little or no immunoglobulin and complement deposition), also called necrotizing crescentic or rapidly progressive glomerulonephritis. Granulomas can be observed in up to 20% of patients. The extent of lesions is associated with renal recovery after treatment [61]. Focal glomerular lesions (>50% of normal glomeruli) and crescentic categories (crescent in >50% of the glomeruli) have a better prognosis than do sclerotic (>50% of glomeruli) or mixed categories.

Nerve, muscle, and/or neuromuscular biopsies (mainly of the branches of the peroneal nerves) can show vasculitic

Fig. 8.12  A lung biopsy in a patient with granulomatosis with polyangiitis. Histiocytes line a microabscess with central basophilic necrosis involving the small artery (center); scattered giant cells (upper and lower right) are also present (Hematoxylin and eosin; 100×). (Courtesy of Dr. Carol Farver, Cleveland Clinic, OH)

features in up to 60% of patients with clinical symptoms of peripheral neuropathy but are rarely necessary for a diagnosis and should be avoided because they carry a risk of permanent neurological (sensory) damage around the site of biopsy. A temporal artery biopsy in case of headache can be considered; temporal artery involvement has been described [111].

Di erential Diagnosis

The main differential diagnoses of GPA are listed in Table 8.5. Besides other systemic vasculitides, secondary vasculitis to other systemic diseases, granulomatous diseases (sarcoidosis, Liebow’s lymphomatoid granulomatosis, beryllium disease, Crohn’s disease), IgG4-related diseases, infections (especially tuberculosis and fungal infections), or malignancies (mainly primary or metastatic lung cancers) can mimic GPA.

Pulmonary renal syndrome is not the hallmark of GPA or microscopic polyangiitis and can also occur in systemic lupus erythematosus and anti-GBM disease. However, one should keep in mind the possible association of the latter with GPA (patients with high titers of both ANCAs and anti-­ GBM antibodies). Saddle nose deformity, although highly suggestive, is not specifc of GPA. It can occur in relapsing polychondritis, sarcoidosis, T-cell/NK lymphomas (centrofacial angiocentric lymphomas), congenital syphilis or other acquired and eroding infections like mucormycosis or leprosy, or after nasal traumas. Cocaine-levamisole-induced vasculopathy is another important differential for patients

Table 8.5  Main differential diagnoses of granulomatosis with polyangiitis (Wegener’s granulomatosis)

Other vasculitides

ENT ear, nose, and throat, GBM glomerular basement membrane, HLA human leukocyte antigen, TAP1 antigen peptide transporter 1

a Now classifed as a primary vasculitis in the revised 2012 Chapel Hill nomenclature (cf. Table 8.1)

with multiple and necrotic skin and ENT eroding lesions, with massive nasal septum perforation and/or frequent soft palatus perforation, which is not common in GPA. Other drugs, including propylthiouracil or minocycline, can induce vasculitis or several vasculitic features, most of the time associated with atypical or MPO-­ANCAs rather than PR3-ANCAs.