Page 296 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

270 Elizabeth J. Brant, Julie G. McGregor, J. Charles Jennette et al.

this question. Complete depletion of peripheral B-cells cannot continue indefinitely if
toxicities associated with immunosuppression are to be avoided. Targeted depletion of only
B-cells with the future capacity to produce pathogenic ANCA would be ideal. To this end,
there are data suggesting that patients with active disease have a lower percentage of CD5+
B-cells compared to patients in remission, and that rituximab-exposed patients who have a
robust reconstitution of CD5+ B-cells after therapy require less immunosuppression [74].

Novel treatment strategies aimed at other components of the inflammatory process, such
as alternative complement pathway activation, are also needed. Alternative complement
activation pathway products in kidney tissue (Bb) and urine (Bb, C3a, C5a, and soluble C5b-
9) of patients with active disease correlate with severity of kidney injury [75]. In the mouse
model of MPO-ANCA glomerulonephritis, blockade of the C5a receptor (C5aR) using an oral
antagonist ameliorates disease in mice expressing human C5aR. [76] At present, a small
clinical trial is underway in Europe to evaluate the safety and efficacy of C5aR blockade to
induce remission in patients with ANCA vasculitis who have mild to moderate kidney
involvement (NCT01363388).

There are several alternative drug options for maintenance immunosuppression, including
azathioprine, mycophenolate mofetil, methotrexate, and leflunomide. Controlled trials of
these various options are limited. A meta-analysis looking at the comparative efficacy of
azathioprine, mycophenolate mofetil, methotrexate, and leflunomide found a 55% probability
that leflunomide is superior to the other three agents for remission maintenance [77].
However, true head-to-head comparisons are lacking. Therefore, provider preference, patient
tolerance, cost, and risk of drug-specific adverse effects all play a role in which medication is
selected.

Outcomes

The presence of kidney disease and its severity at presentation have long been recognized
as important prognostic indicators of renal outcomes in patients with ANCA-associated
vasculitis [78, 79]. A recent study investigating predictors of patient and renal survival in a
Dutch cohort of 273 consecutive patients with ANCA vasculitis followed for almost twenty
years [80] found that overall survival was better in patients without kidney involvement
(hazard ratio [HR] 0.55, CI 0.33-0.92, P = 0.02). Renal survival was worse in MPO-ANCA
positive patients (HR 2.1, CI 1.11-3.8, P = 0.01).

A study of 350 patients with AAV evaluated predictors of treatment resistance and
relapse [81]. Altogether, 88% of those enrolled had kidney involvement at or near the time of
diagnosis and followed longitudinally for a median of 49 months. Female or black patients
and those with severe kidney disease appeared to be more resistant to initial therapy.
Increased relapse risk was associated with the presence of lung (HR 1.71, CI 1.04-2.81) or
upper airway disease (HR 1.73, CI 1.04-2.88) and PR3-ANCA positivity (HR 1.87, CI 1.11-
3.14). Most importantly, however, severity of histopathologic findings at diagnosis does not
predict patients for whom treatment would be futile [82].

Complimentary Contributor Copy