Systemic small-vessel vasculitis

Johanna Hamel MD (Dr. Hamel of the University of Rochester has no relevant financial relationships to disclose.)
Andrew Goodman MD (Dr. Goodman of the University of Rochester has received consulting fees from Biogen Idec and Genentech/Roche.)
Anthony T Reder MD, editor. (Dr. Reder of the University of Chicago served on advisory boards and as a consultant for Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Malinkrodt, Serono, and Teva-Marion.)
Originally released May 8, 1995; last updated November 20, 2015; expires November 20, 2018

This article includes discussion of systemic small-vessel vasculitis, systemic vasculitis, Churg Strauss syndrome, granulomatosis with polyangiitis, Wegener granulomatosis, microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


The nomenclature for vasculitis has been updated to account for size of the inflamed vessel, immunopathogenesis, and clinical features. Antineutrophil cytoplasmic antibody-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis affecting small vessels and involving autoantibody formation against the antigens proteinase 3 and myeloperoxidase. While 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 is discussed as are prognostic features. The most recent data on targeted immunotherapies is reviewed with regards to induction of remission and maintenance treatment as well as 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 microscopic polyangiitis and EGPA), with different phenotypes and treatment responses, depending on the subtype.


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


• Treatment with immunosuppressants 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 GPA and 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

Previously, 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 (Churg and Strauss 1951).

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, therefore, was a significant advance (van der Woude et al 1985) not only for characterization of different types of vasculitis but also for their role in disease pathogenesis; utility as a biomarker continues to be investigated.

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,” abbreviated GPA (Jennette et al 2011). Churg-Strauss syndrome has now been recognized by the 2012 revised nomenclature for vasculitides as “eosinophilic granulomatosis with polyangiitis” and based on the association with ANCA antibodies, combines the group of ANCA-associated vasculitis together with granulomatosis with polyangiitis and microscopic polyangiitis.

In 2012 at the Chapel Hill Consensus Conference, noninfectious (aseptic) vasculitides were further classified based on the immunopathology and predominantly affected vessel size (Jennette 2013; Jennette et al 2013):

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. (One of the goals of the DCVAS study is to develop diagnostic criteria for the primary systemic vasculitides, NCT01066208; its anticipated completion date is December 2015.) Lastly, 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. Data continues to evolve with regards to targeted immunotherapies, especially rituximab for induction of remission and maintenance treatment.

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