At a Glance

Anti-neutrophils cytoplasmic antibodies (ANCA) are associated with a group of necrotizing small vessel vasculitides that usually have a paucity of vascular deposition of immunoglobulin and complement. This distinguishes ANCA associated disease from disease caused by anti-glomerular membrane antibodies and disease caused by immune complexes, both of which have deposition of pathogenic immune complexes in vessel walls. ANCA associated vasculitides include Wegener granulomatosis (WG), Microscopic polyangiitis (MPA) and its renal limited form, and Churg-Strauss syndrome (CSS).

Wegener granulomatosis

Granulomatous inflammation involves the respiratory track and necrotizing vasculitis affecting small to medium size vessels (venules and arterioles). It is characterized by a lack of eosinophilia in blood and biopsy samples. It can occur in two forms:

systemic disease, which includes necrotizing glomerulonephritis

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a limited form in which the disease is localized to the upper and lower respiratory track

Clinical symptoms usually include a prolonged prodrome of malaise, arthralgia, and myalgia. Patients can present with a dry cough, hemoptysis, bilateral diffuse lung infiltrate revealed by a chest X ray, sinusitis, otitis, cutaneous vasculitis, or a rapidly progressive glomerulonephritis.

Microscopic polyangiitis

This is a disease characterized by necrotizing vasculitis affecting small vessels. Necrotizing glomerulonephritis is very common; pulmonary capillaritis is often present. Usually, there is a lack of granulomatous inflammation in the respiratory track in biopsy samples. Symptoms are relatively sudden with a short prodrome of malaise, fever, arthralgia, and myalgia, followed by a rapidly progressive glomerulonephritis. Other extra-renal symptoms may include cutaneous vasculitis or mononeuritis multiplex. Pulmonary manifestations, including pulmonary hemorrage, can also be present.

Churg-Strauss syndrome

This is a disorder marked by eosinophil-rich and granulomatous inflammation involving the respiratory track and necrotizing vasculitis involving small to medium size vessels. Most patients have asthma or history of allergies. Onset of vasculitis is often preceeded by malaise and fever. Systemic features can include cutaneous vasculitis lesions, neuropathy, paranasal sinus abnormality, or pulmonary infiltrates.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

ANCA are the most important laboratory tests used to confirm the diagnosis of this group of vasculitides. ANCA are a heterogeneous group of autoantibodies, including antibodies with specificity for proteinase 3 (PR3) and myeloperoxidase (MPO). A C-ANCA pattern identified by indirect immunofluorescence staining of neutrophils (diffuse staining of the cytoplasm sparing the nuclei) usually correlates with PR3-ANCA. Although a P-ANCA (peri-nuclear staining) is usually associated with MPO-ANCA, antibodies specific for elastase, cathepsin G, and lactoferrin are also associated with P-ANCA.(Table 1)

Table 1.
ANCA-associated vasculitides PR3-ANCA sensitivity (%) MPO-ANCA sensitivity (%)
Wegener granulomatosis 70-80 10
Microscopic polyangiitis 30 60
Idiopathic crescentic glomerulonephritis 30 64
Churg-Strauss syndrome <5 40

Kallenberg CG, Heeringa P, Stegeman CA, et al. Mechanisms of disease: pathogenesis and treatment of ANCA-associated vasculitides. Nat Clin Pract Rheumatol 2006;2:661-670.

C-ANCA plus with anti-PR3 are sensitive markers for WG. Extra-renal organ manifestations and respiratory track granulomas occur more frequently in patients with anti-PR3 than those with anti-MPO. P-ANCA with anti-MPO reactivity is less frequently found in WG and is associated with less organ involvement.

ANCA alone is not sufficient to make or exclude the diagnosis of WG. Sensitivity of PR3-ANCA may be as low as 65% in patients with limited WG or inactive disease.

A marked peripheral blood eosinophilia is an important criteria for the diagnosis of CSS.

Disease should be monitored with serial measurements of ANCA titers. ANCA titers do not correlate with the degree of disease activity. Rising titers may indicate a relapse, but not always. ANCA titers alone can serve as a warning signal, but not as an indicator whether to adjust or initiate treatment.

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?

ANCA test results should be interpreted cautiously. The interpretation of the antibody staining pattern using indirect immunofluorescence can be complicated by the presence of other antibodies. In particular, P-ANCA may be difficult to interpret, because anti-nuclear antibodies (ANA) may produce similar staining patterns on neutrophil nuclei. A P-ANCA pattern should not be reported, unless the specimen has been evaluated for the presence of ANA and/or the test has been repeated using formalin fixed slides in addition to ethanol fixed slides.

What Lab Results Are Absolutely Confirmatory?

In addition to ANCA testing, confirmation of the diagnosis should include biopsy. Renal biopsy usually shows pauci-immune necrotizing glomerulonephritis; a biopsy of the lung, sinuses, or nerve will show vasculitis often with fibrinoid necrosis. Necrotizing granuloma is seen in WG and CSS, but not in MPA.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Other laboratory tests should include erythrocyte sedimentaion rate (ESR)/C-reactive protein (CRP), serum creatinine, and urinalysis.

Disease should be monitored with serial measurements of ESR/CRP, serum creatinine, and urinalysis.

Exclusion tests may include complement C3 and C4, anti-GBM, ANA, anti-dsDNA, anti-Sm/RNP, and anti-SSA/SSB.

What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Atypical P-ANCA can be seen in patients with drug-induced vasculitis or in autoimmune diseases, such as systemic lupus erythematosus (SLE). However, these P-ANCA are usually against elastase or lactoferrin and not against MPO or PR3, which are associated with WG and MPA. Since most forms of vasculitis can affect the skin, it is important to identify those with underlying severe systemic disease, such as ANCA-associated vasculitis or Periarteritis Nodosa (PAN), to initiate appropriate treatments.