Clinical features and diagnosis of small-vessel vasculitis

Vasculitis refers to inflammation of the blood vessel. This inflammation can cause vessel wall thickening that compromises or occludes the vessel lumen, ultimately resulting in organ ischemia. It also can cause vessel wall attenuation that predisposes to aneurysm formation or breach of the vessel integrity with resultant hemorrhage into the tissue.

Vasculitis can be thought of as a primary or secondary process. Primary vasculitides are unique disease entities without a currently identified underlying cause in which vasculitis forms the pathologic basis of tissue injury. Vasculitis can occur secondary to medication exposure or an underlying illness, including infections, malignancy, cryoglobulinemia, and rheumatic diseases (such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, or myositis).

Primary vasculitides may differ in epidemiology, such as the age at which they occur and the gender most likely to be affected, their clinical manifestations (including signs, symptoms, and patterns of organ involvement), the diagnostic approach (biopsy, arteriography, and laboratory investigation), treatment (supportive care, glucocorticoids alone, or in combination with other immunosuppressants), and the size of the vessels predominantly affected (large, medium, or small).

Small-vessel vasculitis affects the arteriole, capillary, and venule. An excellent example of small-vessel vasculitis and the one most commonly encountered in clinical practice is cutaneous vasculitis, in which extravasation of erythrocytes from disrupted small vessels is observed histologically, with the clinical sequelae of palpable purpura. Although categorization based on the predominant vessel size that is affected is a helpful way to view these diseases, this is not absolute and each disease has the potential to affect a diverse range of vessels.

This article explores the clinical features and diagnosis of three forms of vasculitis that predominantly affect the small vessels: granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome, EGPA).

GRANULOMATOSIS WITH POLYANGIITIS

Granulomatosis with polyangiitis is characterized by granulomatous inflammation involving the respiratory tract and by vasculitis affecting small- to medium-sized vessels in which necrotizing glomerulonephritis is common.

Wide range of presentations, manifestations

Approximately 90% of patients with GPA have upper or lower airway involvement or both.¹ Upper airway or ear symptoms affect 73% of patients initially and 92% overall.¹ Direct inspection of the nasal membranes shows a cobblestoned or ulcerated appearance, and computed tomography reveals mucosal thickening of the sinuses. In some instances, sinus disease can compromise blood supply to the cartilaginous portion of the nasal septum, leading to nasal septum perforations or collapse of the nasal bridge. Another manifestation of upper airway disease and GPA is subglottic stenosis, a narrowing in the subglottic region located just below the vocal cords. The narrowing typically spans about 1 cm and rarely extends or involves the remainder of the trachea.

The lungs are involved in 85% of patients.¹ Radiographic abnormalities can be diverse and include bilateral pulmonary nodular infiltrates, single or multiple cavities, and bilateral ground glass infiltrates as can be seen in pulmonary hemorrhage (Figure). Bronchoscopy may reveal endobronchial stenosis, and pleural disease can occur rarely.

Approximately 20% of patients with GPA may have glomerulonephritis when they first present for medical attention, but it eventually develops in nearly 80% of patients during the disease course.¹ Despite its potential for rapid progression, glomerulonephritis presents a diagnostic challenge because it is asymptomatic. It is detected by evidence of proteinuria and an active urine sediment with dysmorphic red blood cells and red blood cell casts.

Ocular involvement occurs eventually in 52% of patients with GPA.¹ Any ocular structure can be affected and ocular involvement can be visually threatening. The more prominent ocular manifestations include scleritis/episcleritis or orbital disease.

Cutaneous manifestations, observed in 46% of patients, include verrucous-appearing lesions on the elbow and infarctions in the skin and nail folds.¹ Other rare manifestations can occur, such as pericarditis and cerebral vasculitis.

Although nearly all patients present with upper or lower airway symptoms, the multisystem nature of GPA explains the wide range of presentations and the varying degrees of disease severity.

Differential diagnosis

The differential diagnosis in GPA is varied. Particularly in the setting of isolated lung or sinus disease, infection is foremost in the differential diagnosis. Even in the nonimmunosuppressed host, unusual infections such as mycobacteria, histoplasmosis, and other fungal infections should be considered. Lymphadenopathy, rarely seen in GPA, should raise concern for other causes of disease. Lymphoproliferative processes and other neoplasms, other rheumatic diseases, granulomatous disease (ie, sarcoidosis), and other causes of glomerulonephritis (when present) also merit consideration. Differentiation of these entities from GPA is essential because the treatment differs in many instances.

The differential diagnosis for patients who present with midline destructive lesions must include other causes of collapse of the nasal bridge, nasal septum perforation, and possibly palate destruction. Erosions of the hard palate in particular should raise an immediate red flag for entities other than GPA, such as lymphoproliferative diseases; rare infections, particularly if the patient has studied or worked abroad; and cocaine exposure.

Diagnostic evaluation

A diagnosis of GPA is typically based on the presence of histologic features in a clinically compatible setting. Diagnostic features include necrosis, granulomatous inflammation, vasculitis, and special stains and cultures negative for microorganisms.

Biopsy sites are determined by evidence of clinical disease affecting a target organ and the likelihood of obtaining diagnostically meaningful findings from that site. One challenge is that biopsies are not always diagnostic. The changes tend to be patchy and the likelihood of a positive yield is associated with the amount of tissue that can be obtained. Tissues from the ear, nose, and throat have a yield of about 20%, depending upon the site and the biopsy size. The highest yield comes from radiographically abnormal pulmonary parenchyma. Although transbronchial biopsies are attractive because they are less invasive than open lung biopsy, they are also far less diagnostic, with fewer than 10% having a positive yield. Because cutaneous vasculitis is observed in many settings, its presence is usually insufficient evidence for diagnosis. The renal histologic appearance is a focal, segmental, crescentic, and necrotizing glomerulonephritis that has few to no immune complexes (pauciimmune glomerulonephritis).^1–3

Chest imaging should be performed in any patient in whom GPA is part of the differential diagnosis, since up to one-third of patients may be asymptomatic yet have pulmonary radiographic findings.

Laboratory assessment should include serum chemistries to evaluate renal and hepatic function, complete blood count, erythrocyte sedimentation rate, measurement of C-reactive protein, and urinalysis. If the urinalysis is positive for blood, microscopy should be performed on fresh urine to look for casts. In the setting of pulmonary-renal manifestations, testing for other causes, such as antiglomerular basement antibodies and antinuclear antibodies, should be considered.

Serologic testing for antineutrophil cytoplasmic antibodies (ANCA) has provided a useful tool in suggesting the diagnosis of GPA. Two forms of ANCA have been identified in patients with vasculitis: ANCA directed against the neutrophil serine protease proteinase-3 (PR3), which results in a cytoplasmic immunofluorescence (cANCA) pattern; and ANCA directed against the neutrophil enzyme myeloperoxidase (MPO), which causes a perinuclear immunofluorescence (pANCA) pattern.⁴ Approximately 80% to 95% of ANCA found in patients with active severe GPA are detectable PR3-cANCA, while 5% to 20% are MPO-pANCA.⁵ The predictive value of ANCA for the diagnosis depends on the spectrum of clinical features. As ANCA can be seen in other settings, ANCA as the basis for diagnosis in place of tissue biopsy should be used with caution and only in selected instances where their predictive value would equal that of biopsy. The presence of ANCA is not necessary to establish the diagnosis, as up to 20% of patients with GPA may be ANCA-negative.⁶