Urological Manifestations

Ureteral (or, less frequently, urethral) stenosis, unior bilateral, single or multifocal, secondary to ureteral arteriolitis, peri-ureteral granulomatous infltrates, and/or sheathing in retroperitoneal fbrosis can occur and cause hydronephrosis and/or obstructive renal insuffciency [63]. Granulomatous prostatitis, ischemic and/or granulomatous orchitis, and penile ulcers have been reported [63]. Vulvar ulcerations have been reported in women.

Bladder involvement is rare, and in ammation and/or hematuria originating from the bladder should suggest an infection and/or hemorrhagic cystitis in patients receiving cyclophosphamide, bladder cancer in those receiving cyclophosphamide, and/or in heavy smokers [65].

Neurological Manifestations

Peripheral Nervous System (PNS) Manifestations

The peripheral nervous system (PNS) is affected in 11–68% of patients [66]. Clinically, mononeuritis multiplex (asymmetrical and asynchronous) represents the principal pattern of peripheral nervous system involvement (45–79% of cases), most frequently involving the ulnar and peroneal nerves, followed by sensorimotor (symmetrical) polyneuropathy, both related to axonal ischemia due to vasculitis of the vasa nervorum of the small epineurial vessels.

Central Nervous System (CNS) Manifestations

The central nervous system is more rarely involved in 6–13% of patients and often later and more progressively (except for the exceptional strokes) than the PNS [67, 68]. Central nervous system involvement can result from the extension of sinus and/or orbital granulomatous lesions, causing pachymeningitis and sometimes (postor pan-) pituitary gland involvement (diabetes insipidus) or a new development of cerebral granulomatous lesions and/or intracranial artery vasculitis. Headache, meningeal irritation, cranial nerve palsy, hypoacousia, and sensorimotor defcit are the most frequent clinical features, but hemiparesis, hemiplegia, or seizures can also occur (usually ischemic). Rare cases of cerebral venous thrombosis with cortical venous infarction have been reported.

Spinal Cord and Cranial Nerve Involvement

Spinal cord or cauda equina involvement is rare and is usually due to compression by a meningeal granulomatous infltrate rather than spinal cord ischemic vasculitis [69]. Cranial nerve involvements are more common (4–14% of patients), primarily affecting the optic nerves II, VI, and/or VII and V, unior bilaterally, and occur due to compression by extensive meningeal or pseudotumoral intraorbital lesions or, more rarely, nerve ischemia and/or in ammation.

Fig. 8.10  Diffuse ecchymotic, necrotic, and purpuric lesions in a patient with granulomatosis with polyangiitis

Skin and Oral Mucosal Manifestations

In total, 10–50% of patients have skin lesions, primarily palpable purpura (Fig. 8.10). Macules, papules, ulcers, digital gangrene, or, more rarely, subcutaneous nodules can occur [70]. Palpable purpura is more common in the lower extremities, but involvement of the elbows (nodules, ulcerated nodules) and hands, including the dorsal face and digital pulps, is not infrequent. Lesions can sometimes mimic erythema elevatum diutinum, pyoderma gangrenosum, or hidradenitis suppurativa, which can also occur as a rare complication or an associated condition.

Skin biopsies most often reveal nonspecifc perivascular infltrates and/or aspects of leukocytoclastic vasculitis of small vessels, which are not specifc to GPA. Sometimes, blatant necrotizing vasculitis of superfcial vessels of the dermis and/or deep subcutaneous layers is seen. Vascular or extravascular granulomatous infltrates can be seen in nodular or papular lesions [71].

Oral mucosal lesions can occur in 10–50% of patients and include ulcerations; persistent canker sores, especially on the lateral edges of the tongue; and gingival hypertrophy or “strawberry” gum, which is often painful and relatively evocative of GPA [70]. Infltrations of the parotid and/or accessory salivary glands have been described. Very destructive lesions of the soft palate are rare in GPA, and more suggestive of levamisolecocaine induced GPA-like vasculitis/vasculopathy.

Eye Manifestations

Ocular and/or orbital manifestations are relatively common (14–60% of patients) and can be inaugural and/or remain isolated for a long time.

Proptosis, possibly associated with ophthalmoplegia, is usually due to the local extension of a granulomatous retro-­ orbital tumor or from the ear, nose, throat, and/or meningeal lesions (Fig. 8.11).

Fig. 8.11  A sinus and orbital CT scan (coronal) in a patient with granulomatosis with polyangiitis. Massive infltration of the left orbital cavity by a tumoral tissue (likely granulomatous on biopsy and exerting compression on the eye and ocular muscles)

Conjunctivitis and episcleritis are relatively common and benign. In ammation of the lacrimal gland (dacryocystitis or dacryoadenitis) is also common and leads to dry eye sensation, watery eyes, or suprainfection because of clogged tear ducts, which may require surgical debridement procedure and/or stenting. Corneal ulcers and scleritis, often necrotizing and nodular, are more of a concern because of the risk of eye perforation, loss of vision, and endophthalmitis. Retinal vasculitis is rarer but can also cause blindness [72]. Extensive xanthelasma has been reported, especially after the regression of an orbital tumor [70].

Cardiac Involvement

Cardiac involvement is rare (about 10% of patients but up to 30% in an autopsy series) [73, 74]. Magnetic resonance imaging (MRI) or sophisticated echocardiography (such as two-dimen- sional (2D) speckle-tracking) of the heart or electrophysiological investigations can reveal subclinical abnormalities, the prognostic value of which remains to be determined [75].

Sinus tachycardia is common during the active phases of the disease, as are arrhythmias, especially atrial fbrillation. Conduction disorders due to granulomatous infltration of the cardiac conductive tissue can lead to an atrioventricular block or a bundle branch block, which may require transient pacing but usually regresses with medical treatment. Pericarditis, sometimes progressing to tamponade and/or constrictive pericarditis, and coronary artery in ammation, most often clinically silent, account for half of the reported cardiac manifestations in GPA. Myocardial infarction, diagnosed during the patient’s life, represent about 10% of the reported cases of GPA, with cardiac involvement and valvular disease, primarily aortic, in 21% of such cases [74].

Gastrointestinal Manifestations

Gastrointestinal manifestations are less frequent in GPA than in other mediumand small-sized vessel vasculitides and are rarely isolated or present at disease onset; they range from mild abdominal pain to more severe ischemic bowel perforations [76, 77]. In ammatory granulomatous ileocolitis, gastritis, or anorectitis are more characteristic but are not specifc (differentiating between GPA, Crohn’s disease, and ulcerative colitis can be diffcult). Biopsies performed endoscopically rarely reveal vasculitis (10–50%) and are not without risks.

The involvement of the appendix or pancreas (sometimes with challenging tumoral presentation) and/or the gallbladder has been reported [78]. Hepatic involvement is rare in clinical practice and usually remains limited to laboratory abnormalities (transaminitis). Splenic involvement is exceptional but can be responsible for infarction or a nontraumatic rupture. Hepatic artery aneurysms, which can rupture, have been reported.

Gynecological and Obstetric Manifestations

Few cases of mastitis have been described but can present as breast masses or ulcerated skin lesions. Uterine and vulvar lesions are rare.

Few pregnancies in GPA patients have been reported in the literature, in part because the average age of onset of the disease is about 45 years and because cyclophosphamide, often used as treatment, can lead to infertility or subfertility in women of childbearing age, depending on the cumulative dose received [79, 80]. Decreased fertility resulting from the disease itself is possible, but overt ovarian involvement has rarely been described. Measurement of the anti-Mullerian hormone at treatment onset (and thereafter) can help evaluate the remaining follicles in young women.

Few women develop GPA during pregnancy, and few others with known GPA experience disease ares or worsening during pregnancy post-partum or post-abortion [81–83], some with fatal outcome. However, more than half of the reported pregnancies with GPA have been uneventful or with only minor disease manifestations. The risk of GPA worsening or relapse is an estimated 25% if the disease is in remission at the onset of pregnancy and is 40% if the disease is active. The existence of organ damage from previous ares, especially renal and/or heart failure, must be taken into consideration when evaluating the risk with pregnancy. GPAares and complications during pregnancy must be managed in referral centers for vasculitis and high-risk pregnancies.

Among pregnancies carried to term with GPA, newborn and child outcomes appear to be favorable, perhaps with a slightly higher frequency of preterm deliveries [80, 81].

Venous Thrombosis and Other Vascular Events

Many studies have now reproducibly demonstrated an increased risk of venous thromboembolic events (deep vein thrombosis and/or pulmonary embolism) with GPA, mainly during the active phases of the disease [84–88]. The incidence of these events was an estimated 7 per 100 patient-­ years in one of the frst studies reporting this complication, which is a 20-fold higher risk than in the general population [85]. The events are probably favored by systemic and vessel wall in ammation and frequent, reduced patient mobility because of the disease and/or neuropathy in some patients. Additional autoimmune mechanisms may lead to the development of these thromboses (antibodies against plasminogen have been detected in some patients, and PR3-ANCAs may cross-react with plasminogen in certain conditions) [89].

Besides digital ischemia, stroke, and/or coronary artery involvement, limb ischemia or carotid artery thromboses can occur, although rarely [90]. A few cases of ascending aorta in ammation (aortitis), pseudotumor (periaortitis), or aneurysms of the aorta, subclavian arteries, popliteal, renal, hepatic, and/or spleen have been reported. There is also an increased risk of ischemic heart disease, possibly because of endothelial function abnormalities, some of which are reversible in part with immunosuppressive therapy and prolonged use of glucocorticoids [91].

Other Manifestations

Other rare manifestations include periostitis, almost exclusively of the tibia, or prevertebral dorsal lesions, which can mimic fbrosing mediastinitis but are usually not erosive or compressive [92, 93]. Retroperitoneal fbrosis is exceptional and should raise suspicion of a IgG4related disease.

Granulomatous involvement of the thyroid gland is rare, but autoimmune hypothyroidism (Hashimoto) or hyperthyroidism (Graves’ disease) can occur. Other endocrine glands that can be affected include the adrenal and pituitary glands (as described with CNS manifestations). Pancreatic involvement does not usually result in secondary diabetes mellitus.

Limited/Localized Versus Severe/Di use/

Systemic Forms

Despite the variation in defnitions among studies and authors (Table 8.3), GPA can be differentiated into two