At a Glance
Vasculitis is an inflammation of the blood vessel wall. The various systemic vasculitides are often categorized based on the size of the involved blood vessels, namely small, medium, and large vessels. Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) are referred to as small-vasculitides. They are also known as ANCA-associated vasculitides because of their association with a group of neutrophil-specific autoantibodies. The three disorders are all characterized by involvement of the upper respiratory tract, the lungs, and the kidneys, although with different specific manifestations.
Clinical Manifestations of Wegeners Granulomatosis
WG is a granulomatous necrotizing vasculitis affecting small- to medium-sized vessels.
In WG, clinical manifestations in the upper respiratory tract may include stuffiness, epistaxis, and/or damage to the cartilage, sometimes leading to saddle-nose deformity. With regard to lung disease, patients may present with dyspnea, cough, and/or chest pain. On chest X-ray, the most commonly observed abnormalities associated with WG are pulmonary infiltrates, which may initially be diagnosed as pneumonia and nodules. In some cases, these findings may be incidental and the patient may be asymptomatic. A smaller number of patients may present acutely with alveolar hemorrhage, which is associated with alveolar capillaritis. Symptoms involving the upper and/or lower respiratory tract are estimated to occur in 90% of patients with WG.
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For patients with renal disease, clinical manifestations are characterized by a rapidly progressive glomerulonephritis, including proteinuria, hematuria, and presence of cellular casts. Estimates suggest 20% of patients with WG present with kidney dysfunction, although 80% ultimately progress to renal disease.
Lastly, it is important to recognize that other organ systems, including the skin, nervous system, and gastrointestinal (GI) tract, may also be involved in WG, although at lower frequencies.
Clinical Manifestations of Microscopic Polyangiitis
Microscopic polyangiitis (MPA) is a necrotizing vasculitis with few or no immune deposits that primarily affects the small vessels, although involvement of medium-sized arteries may be observed. The most common organ involved in MPA is the kidney.
Like WG, the primary clinical manifestation is a rapidly progressive glomerulonephritis. Renal disease may be accompanied by involvement of other organ systems, including the lungs, skin, and nervous system. Alveolar hemorrhage associated with capillaritis is the most frequent pulmonary manifestation. Mononeuritis multiplex may also be observed in a subset of patients. In contrast to WG, involvement of the upper respiratory tract is infrequently observed in patients with MPA and with significantly milder symptoms.
Clinical Manifestations of Churg-Strauss Syndrome
Churg-Strauss syndrome (CSS) is a necrotizing vasculitis of the small- and medium-sized vessels that is associated with asthma and eosinophilia. Pulmonary involvement, specifically asthma, is a common manifestation of CSS. Upper respiratory tract symptoms may also occur, often in the form of allergic rhinitis or nasal polyps. Mononeuritis multiplex occurs more frequently in patients with CSS compared to patients with WG or MPA.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
WG, MPA, and CSS are classified as anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides because of their association with autoantibodies specific for proteins within the granules of neutrophils. ANCAs are measured in the clinical lab by a combination of immunfluorescent assays (IFAs) and enzyme immunoassays (EIAs). IFAs generally use ethanol-fixed neutrophils as the substrate tissue.
In the context of the vasculitides, two different patterns may be observed by IFA, which are referred to as cytoplasmic ANCA (cANCA) or perinuclear ANCA (pANCA). The cANCA pattern is associated with the presence of an antibody specific for the enzyme proteinase 3 (PR3). In contrast, the pANCA pattern may be associated with an antibody specific for myeloperoxidase (MPO). Testing for antibodies specific for PR3 and MPO is performed using EIAs, with purified PR3 or MPO as the capture antigen and a labeled anti-human IgG as the detection antibody. (Table 1)
Table 1
| Wegener’s Granulomatosis | Microscopic Polyangiitis | Churg-Strauss Syndrome |
|---|---|---|
| Positive for PR3 antibody by EIA and cANCA pattern by IFA | Positive for MPO antibody by EIA and pANCA pattern by IFA | Positive for MPO antibody by EIA and pANCA pattern by IFA |
ANCA Testing
WG is associated with antibodies specific for PR3 and a cANCA staining pattern by IFA. Approximately 80-90% of patients with active WG are positive for PR3/cANCA.
MPA is associated with antibodies specific for MPO and a pANCA staining pattern by IFA. Approximately 75% of patients with active MPA are positive for MPO/pANCA.
CSS is associated with antibodies specific for MPO and a pANCA staining pattern by IFA. Approximately 50% of patients with active CSS are positive for MPO/pANCA.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
The cANCA pattern is distinct and readily identified by an immunofluorescence assay (IFA) using ethanol-fixed neutrophils. A cANCA pattern observed by IFA almost always correlates with an anti-PR3 antibody detected by enzyme immunoassay. In contrast, the pANCA pattern correlates less with the presence of an anti-MPO antibody. It is not uncommon to identify a pANCA pattern by IFA in the absence of an anti-MPO antibody, because antibodies specific for other antigens, such as neutrophil elastase, show the same pANCA staining pattern as an MPO antibody. One common interfering antibody is the anti-nuclear antibody (ANA). Depending on the antigen specificity, the presence of an ANA may be interpreted as a pANCA on ethanol-fixed neutrophils.
pANCAs are associated with disorders other than MPA and CSS, including inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and primary sclerosing cholangitis. However, the antigen specificities of the pANCA have not been defined for these disorders, and the diagnostic utility of this testing in these disorders is limited.
What Lab Results Are Absolutely Confirmatory?
Autoantibody testing alone cannot be relied on to establish a diagnosis for any of the ANCA-associated vasculitides. In most cases, a biopsy is required to confirm the diagnosis in the context of positive antibody serology and compatible clinical symptoms.
Biopsy Findings
Although any affected tissue can be useful for pathological evaluation, lung tissue is the most common site for biopsy and may provide the most useful diagnostic information. In lung tissue, it may be possible to identify the vasculitic process, as well as the subsequent necrotizing granulomas. Features associated with granulomas include palisading histiocytes, scattered giant cells, and areas of necrosis. Renal biopsies may also be useful in patients with kidney dysfunction. On pathology, the most common lesion observed is a segmental necrotizing glomerulonephritis with crescent formation. In addition, the lesions are characterized as pauci-immune because of lack of immunoglobulin or complement deposition.
Because of the strong association with renal disease, most biopsies for evaluation of MPA are taken of the kidneys. As with WG, a finding of segmental crescentic necrotizing glomerulonephritis is consistent with MPA. Because the biopsy findings are so similar, distinction between MPA and WG is made based on clinical presentation and ANCA test results.
Peripheral blood hypereosinophilia is a characteristic finding for CSS. On a complete blood count (CBC) with differential, greater than 10% eosinophils of the total leukocyte count is consistent with a diagnosis of CSS. In addition, the presence of eosinophils in the extravascular space can also support a diagnosis of CSS.
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