Page 48 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

24 David S. Younger

Instead, a focal, segmental glomerulonephritis is often seen. Other inflammatory or vasculitic
phenomenon can be encountered such as leukocytoclastic vasculitis in skin lesions, and acute
and chronic inflammation in sinus, retro-orbital, and tracheal tissues. A limited form of GPA
without glomerulonephritis was described [51] that was a long-term disease stage or
phenotype accounting for about 5% of all patients characterized by destructive and space-
consuming lesions associated with relapse rates of 46% and local damage [52].

The 1990 ACR criteria for the classification of GPA [53] which preceded routine ANCA
testing, included the presence of two or more from criteria from among four including nasal
or oral inflammation (painful or painless oral ulcers or purulent or bloody nasal discharge);
abnormal chest radiograph (showing nodules, fixed infiltrates or cavities); urinary sediment
(showing microhematuria >5 red blood cells per high power field, or red cell casts in urinary
sediment); and granulomatous inflammation on biopsy tissue (within the wall of an artery or
in the perivascular or extravascular area of an artery or arteriole).

A proposed classification tree substituted hemoptysis for granulomatous inflammation on
a tissue biopsy if the latter was not available. Baseline serum samples for 180 participants in
the WG Etanercept Trial Research Group (WGET) found that when IF, direct and capture
ELISA ANCA testing were performed at baseline, 166 (92%) were seropositive, including
96% with severe disease and 83% with limited disease.

Holle and colleagues [54] who prospectively compared a highly sensitivity (hs)PR3-
ANCA ELISA to the IFT noting an excellent performance of the hsPR3-ANCA ELISA in
identifying GPA and other AAV disorders associated with PR3-ANCA suggesting that the
former by used as screening test. Since the early observations of ANCA provided by van der
Woude and colleagues in 1985 [55], and Falk and Jennette [56] and Goldschmeding and
colleagues [57], and ensuing progress in the differentiation and understanding of ANCA
subtypes [58], the past quarter century has witnessed a renaissance in the understanding of
primary systemic vasculitis with convincing clinical evidence to support an important role for
ANCA in the development of AAV. An AAV classification appears to better recognize
ANCA disease and predict prognosis than other any existing clinical classification systems
[59].

However as with other autoimmune disorders, the etiology and pathogenesis appears to
be multifactorial, involving the interplay of initiating and predisposing environment and
genetic factors [60-62]. Induction with corticosteroids and either cyclophosphamide followed
by maintenance with rituximab [63-68] or azathioprine [69-71] is recommended treatment.
Among 197 ANCA-positive patients with GPA or MPA in nine centers participating in the
Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN), a
randomized, double-blind, double-dummy, non-inferiority trial [72] comparing rituximab 375
mg per square meter (m2) body-surface area (BSA) per week for 4 weeks to
cyclophosphamide 2 mg per kilogram of body weight per day controls for severe AAV, 67%
of study patients compared to 42% of controls achieved the primary end point of remission of
disease without use of prednisone at six months.

Treatment and efficacy and safety data in children with AAV continue to be largely
derived from adult GPA studies, however as described in ARChiVe, pediatric patients in the
United States and Canada are being offered pulse methylprednisolone for 3 to 5 days,
followed by oral prednisone, and cyclophosphamide orally or with one of two intravenous
regimens, followed by maintenance therapy, most frequently with methotrexate [40].

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