**2. ANCA-associated vasculitis (AAV)**

AAV refers to primary forms of vasculitis targeting the small and medium sized arteries. These were initially differentiated on the basis of clinical features in the 1990 American College of Rheumatology (ACR) classification [1-4]. Further refinements to the classification criteria and new nomenclature have evolved from the initial classification criteria. In 1994, the Chapel Hill Consensus Conference group incorporated vessel size and pathological features to define the different primary vasculitides. They also introduced the use of antibodies to discriminate between vasculitis of the small vessels [5]. Anti-neutrophil cytoplasmic antibodies (ANCA) were initially described in 1985 in patients with segmental necrotizing and crescentic glomer‐ ulonephritis [6] but were later identified in patients with GPA, EGPA and MPA, and are associated with these conditions with high sensitivity and specificity [7].

There are two major types of ANCA recognized by indirect immunofluorescence (IIF). The perinuclear pattern, or P-ANCA, is characterized by immunofluorescence seen at the periph‐ ery of the nucleus of alcohol-fixed neutrophils. The cytoplasmic pattern, or C-ANCA, is characterized by diffuse staining of the cytoplasm. C-ANCA has a specificity for proteinase 3 (PR3), most frequently associated with GPA. P-ANCA has a specificity for myeloperoxidase (MPO), and is most commonly seen in MPA and EGPA.

Although the etiopathogenesis of AAV is not yet well understood, immune system dysregu‐ lation and abnormal inflammatory responses ensue. Therapies which alter immune system signaling and response are used to halt perpetuation of the inflammatory response to prevent end-organ damage and suppress disease activity.

### **3. Outcomes without treatment and determining prognosis**

Because these diseases have a high mortality rate (82% of mortality in GPA at one year without treatment) [8] and relapse frequently (38% of patients with AAV will experience

a relapse within 5 years despite treatment) [9] treatment protocols have reflected the need to obtain rapid control of disease activity and maintain long-term immunosuppression while reducing drug toxicity. This is the basis for an induction phase of treatment to achieve remission followed by a maintenance phase to reduce the risk of relapse. Guille‐ vin et al. developed the Five Factor Score [10] to identify factors associated with poor prognosis at the time of diagnosis. They initially analysed 342 patients with MPA, EGPA and PAN, and the five factors associated with increased mortality were: renal failure with creatinine greater than 140 μmol/L, proteinuria greater than 1 gram/day, cardiac involve‐ ment, central nervous system involvement, or severe gastro-intestinal involvement. In patients with none of these features, the 5 year survival rate was 88.1%. With 1 of these features, the 5 year survival rate declined to 74.1%, and with 2 or more of these features the survival rate was only 54.1%. The analysis of a larger group of 1108 patients with GPA, MPA, EGPA and PAN in 2009 [11] resulted in the identification of new prognosis factors associated with an increase in 5-year mortality rate. These include age > 65 years, cardiac involvement, gastro-intestinal involvement, and renal failure with creatinine >150 μmol/L. The presence of ear, nose and throat symptoms in patients with GPA and EGPA is associated with a lower relative risk of death.

Maintenance of remission is typically with oral cyclophosphamide, azathioprine or metho‐ trexate, with demonstrated efficacy in the CYCAZAREM and WEGENT studies. Leflunomide is also effective, and mycophenolate mofetil is less effective than azathioprine but is an alternative agent should the others not be tolerated. Etanercept therapy does not have a role in maintenance therapy given its inefficacy and toxicity in patients exposed to cyclophospha‐ mide. Other anti-TNF agents, rituximab, Intravenous Immunoglobulin (IVIg), 15-Deoxysper‐ gualin, antithymocyte globulin and alemtuzumab (CAMPATH-1H) have shown some benefit

We conclude the chapter by discussing the use of trimethoprim-sulfamethoxazole (T/S) use in localized disease, as well as a specific focus on the treatment evidence in EGPA with and

AAV refers to primary forms of vasculitis targeting the small and medium sized arteries. These were initially differentiated on the basis of clinical features in the 1990 American College of Rheumatology (ACR) classification [1-4]. Further refinements to the classification criteria and new nomenclature have evolved from the initial classification criteria. In 1994, the Chapel Hill Consensus Conference group incorporated vessel size and pathological features to define the different primary vasculitides. They also introduced the use of antibodies to discriminate between vasculitis of the small vessels [5]. Anti-neutrophil cytoplasmic antibodies (ANCA) were initially described in 1985 in patients with segmental necrotizing and crescentic glomer‐ ulonephritis [6] but were later identified in patients with GPA, EGPA and MPA, and are

There are two major types of ANCA recognized by indirect immunofluorescence (IIF). The perinuclear pattern, or P-ANCA, is characterized by immunofluorescence seen at the periph‐ ery of the nucleus of alcohol-fixed neutrophils. The cytoplasmic pattern, or C-ANCA, is characterized by diffuse staining of the cytoplasm. C-ANCA has a specificity for proteinase 3 (PR3), most frequently associated with GPA. P-ANCA has a specificity for myeloperoxidase

Although the etiopathogenesis of AAV is not yet well understood, immune system dysregu‐ lation and abnormal inflammatory responses ensue. Therapies which alter immune system signaling and response are used to halt perpetuation of the inflammatory response to prevent

Because these diseases have a high mortality rate (82% of mortality in GPA at one year without treatment) [8] and relapse frequently (38% of patients with AAV will experience

for refractory or relapsing disease and require further evaluation.

associated with these conditions with high sensitivity and specificity [7].

**3. Outcomes without treatment and determining prognosis**

(MPO), and is most commonly seen in MPA and EGPA.

end-organ damage and suppress disease activity.

without poor prognostic factors.

190 Updates in the Diagnosis and Treatment of Vasculitis

**2. ANCA-associated vasculitis (AAV)**

### **4. Categorization of disease severity to guide initial treatment agent**

As reflected in the European League Against Rheumatism (EULAR) treatment guidelines [12] the initial immunosuppressive agent choice is dictated by the extent and severity of the disease. The European Vasculitis Study (EUVAS) disease categorisation [13] separates disease severity into localized disease, early systemic disease, generalized, severe and refractory disease.


**Table 1.** Categorization of disease severity to guide initial treatment in anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis [13]

We will now review in detail the evidence for the agents recommended in these treatment guidelines, as well as new evidence arising since their development.
