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  • Updated 06.18.2024
  • Released 05.08.1995
  • Expires For CME 06.18.2027

Systemic small-vessel vasculitis



The nomenclature for vasculitis has been updated to account for size of the inflamed vessel, immunopathogenesis, and clinical features. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. All affect small vessels and involve autoantibody formation against the antigens proteinase 3 and myeloperoxidase. There are no defined diagnostic criteria. The authors discuss management of ANCA-associated vasculitis, including the diagnosis based on clinical manifestations with challenges determining disease activity and damage. The increasing role of antibody markers and prognostic features are discussed. The most recent data on targeted immunotherapies are reviewed with regards to induction of remission, maintenance treatment, and side effects.

Key points

• ANCA-associated vasculitis is the current nomenclature for small-vessel vasculitides, including microscopic polyangiitis (MPA, vasculitis without granulomatosis), granulomatosis with polyangiitis (GPA, vasculitis and granulomatosis but no asthma), and eosinophilic granulomatosis with polyangiitis (EGPA, vasculitis, granulomatosis, asthma, eosinophilia).

• They are associated with antineutrophil cytoplasmic antibodies (ANCA) with specificity against proteinase 3 (predominant in GPA) or myeloperoxidase (predominant in MPA and EGPA). Depending on the subtype, there are different phenotypes and treatment responses.

• The conditions are characterized by formation of granulomas and inflammation of small arteries, arterioles, venules, and capillaries. Inflamed vessels may rupture or become occluded, giving rise to a broad array of clinical symptoms and signs related to a systemic inflammatory response, end-organ microvascular injury, or the mass effect of granulomas (44).

• The most commonly affected tissues are the upper and lower respiratory tract, kidneys, skin, and peripheral nerves.

• Treatment with immunosuppressant therapy is required to induce remission of disease activity, after which patients are transitioned to more gentle maintenance immunosuppression. Two randomized controlled trials (RAVE and RITUXVAS) have shown that rituximab is non-inferior to cyclophosphamide for remission induction in severe granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The RAVE trial also showed superiority of rituximab for patients presenting with a severe disease relapse.

• A randomized trial (MAINRITSAN) showed that rituximab infusions every 6 months were superior to azathioprine as maintenance therapy for PR3 3 ANCA vasculitis.

Historical note and terminology

Historically, vasculitic diseases have been characterized and categorized by their clinical manifestations and often were named after their first discoverer. In 1931, Heinz Klinger described a patient with destructive sinusitis, uremia, granulomatosis of the spleen, glomerular lesions, and arteritis, whom he believed had a variant of polyarteritis nodosa. It was Friedrich Wegener who first recognized this pathologic process as a distinct disease entity in 1936, terming it “rhinogenous granulomatosis.” The name "Wegener granulomatosis" was introduced in 1947, and in 1994, the Chapel Hill Consensus Conference produced the first nomenclature system for Wegener and other idiopathic vasculitides. In 1951, J Churg and L Strauss first described 13 cases with severe disseminated necrotizing granulomatous vasculitis in addition to extravascular granulomas in patients with asthma, fever, and eosinophilia, which then became known as Churg-Strauss syndrome (10).

The trend in vasculitis research is to move towards using accurate, descriptive disease names in place of eponyms, accounting for immunopathogenesis and combining disease entities based on their etiology and treatment response. The discovery of specific ANCA antibodies was a significant advance, not only for characterization of different types of vasculitis, but also for their role in disease pathogenesis and utility as a biomarker (107).

In 2010, the American College of Rheumatology, American Society of Nephrology, and European League Against Rheumatism joined forces to endorse a name change from “Wegener granulomatosis” to “granulomatosis with polyangiitis” (GPA) (50). Churg-Strauss syndrome has now been recognized by the 2012 revised nomenclature for vasculitides as “eosinophilic granulomatosis with polyangiitis” (EGPA) and based on the association with ANCA antibodies, combines the group of ANCA-associated vasculitis together with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

In 2012 at the Chapel Hill Consensus Conference, noninfectious (aseptic) vasculitides were further classified based on the immunopathology and predominantly affected vessel size (47; 47):

1. Large vessel vasculitis

a. Takayasu arteritis
b. Giant cell arteritis

2. Medium vessel vasculitis

a. Polyarteritis nodosa
b. Kawasaki disease

3. Small vessel vasculitides

a. With no immune deposits: ANCA-associated vasculitis (discussed here)
b. With immune complex deposition in the vessel wall

i. Anti-glomerular-basement-membrane disease
ii. Cryoglobulinemic vasculitis
iii. IgA vasculitis (formerly Henoch-Schönlein purpura)
iv. Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)

4. Single organ vasculitis (such as primary central nervous system vasculitis)

5. Vasculitis associated with systemic disease

a. Lupus vasculitis
b. Rheumatoid vasculitis
c. Relapsing polychondritis vasculitis among others

6. Vasculitis associated with probable etiology includes

a. Hepatitis B– and C–associated vasculitis
b. Syphilis-, cancer- or drug-induced vasculitis among others

This classification provides definitions of vasculitis once the diagnosis is made but does not provide diagnostic criteria, which are still in need of development. The finding that combined treatment with cyclophosphamide and prednisone leads to remission in approximately 90% of patients in a disease state once considered fatal was a milestone in treatment and has served as the basis for ever-evolving protocols targeting various stages of the diseases, with greater efficacy and less toxicity.

The current standard management of severe ANCA-associated vasculitis still consists of remission induction therapy with glucocorticoids combined with rituximab or, less often now, cyclophosphamide. Several studies have shown that reduced-dose regimens of glucocorticoids are noninferior to the previously used high-dose regimens for, therefore, less cumulative exposure to glucocorticoids. Avacopan use may even lead to new steroid-free therapeutic approaches, at least for some selected patients (81).

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