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Expanding Therapeutic Tools Encourage Individualized Therapy for ANCA Vasculitis

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Kidney Week - American Society of Nephrology (ASN)

Atlanta, Georgia / November 5-10, 2013

Atlanta - A treatment algorithm is evolving for anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis based on disease severity. Although the therapeutic options remain limited, they have expanded, permitting treatment to be intensified when disease control appears unlikely with first-line steroids and cyclophosphamide. At the 2013 Kidney Week, experts evaluating current best therapies for ANCA vasculitis cautioned that rates of mortality and serious morbidity, such as kidney failure, are concentrated in the first year after diagnosis. This encourages moving rapidly to intensified therapy in patients with severe disease. However, increased disease severity of ANCA vasculitis concentrates in patients with co-morbidities, emphasizing the need to carefully evaluate the expected benefit-to-risk ratio of aggressive treatments when tailoring therapies in response to likelihood of disease progression.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Expanding treatment options for anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has increased the number of targets for inhibiting the pathophysiological cascade that drives this disease. While the standard first-line therapy of steroids and cyclophosphamide may provide a sufficient induction in mild to moderate disease, the risk of rapid deterioration and permanent renal damage encourages more aggressive therapy when disease is severe at presentation. Judicious individualization of treatment with multiple agents may be appropriate.

“There is an upfront mortality rate of 10% to 15%, so the decisions regarding induction are critical,” reported Dr. John Niles, Massachusetts General Hospital, Harvard Medical School, Boston. Outlining the series of steps that leads from upregulation of ANCA-specific circulating B cells to vascular inflammation, he suggested, “we should be thinking more about shutting down all the events at once.” However, this is tempered against the risk of “overdoing it” in patients who are immunocompromised.

Broad Therapeutic Options

The list of treatments for ANCA vasculitis now includes, in addition to oral or pulse steroids and cyclophosphamide (and other immunosuppressive agents such as azathioprine and methotrexate), plasma exchange, intravenous immunoglobulins (IVig), and, most recently, rituximab, an anti-B cell therapy. A reasonable algorithm has begun to emerge from historical precedent and recently completed clinical studies.

The consensus, according to experts at Kidney Week, is that steroids and cyclophosphamide remain first-line therapies because of an extensive evidence of efficacy and low risk of serious adverse events. Other options can be added or substituted depending on assessment of risk of imminent tissue damage. Dr. Niles suggested that rituximab is appropriate for selective use in induction even though it is more commonly reserved for refractory or relapsed ANCA vasculitis. Dr. David Jayne, Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, UK, expressed a similar opinion.

“The RAVE trial demonstrated that rituximab is as effective as cyclophosphamide for induction of new patients, but it is generally preferred when there is a reason to avoid cyclophosphamide,” reported Dr. Jayne, referring to the Rituximab in ANCA-Associated Vasculitis trial (Stone et al. N Engl J Med 2010;363;221-32). For first-line induction, rituximab may be just as effective, but Dr. Jayne suggested that cyclophosphamide is the standard in moderate disease without a rationale for a substitute.

Rituximab Favoured in Randomized Trial

In severe disease, particularly in relapsed patients, the data favour rituximab, according to an update of the RAVE trial (Specks et al. N Engl J Med 2013;369:417-27). Although treatment must still be individualized in the context of risks, the updated RAVE results demonstrated that rituximab is at least as effective in those who are treatment-naïve and more effective in those who have relapsed.

In RAVE, 197 patients with severe ANCA vasculitis defined by vital organ dysfunction that posed an immediate threat to the survival of the organ or the patient, were randomized to rituximab, administered once weekly for four weeks, or daily cyclophosphamide for 3 to 6 months followed by azathioprine for an additional 12 to 15 months. In the initial report, complete remission at 6 months was achieved in 64% randomized to rituximab versus 53% randomized to cyclophosphamide, a result that was non-inferior according to trial design.

In the recently released updated results, remission at 12 months was maintained in 48% of those randomized to rituximab versus 39% of those randomized to cyclophosphamide. The sustained remission rates at 18 months were 39% and 33%, respectively. These overall results again fulfilled the criteria for non-inferiority, but outcomes were superior for rituximab in a subgroup of 101 patients with relapsing disease at baseline. In these, complete remission rates at 6 (67% vs. 42%; P=0.01) and 12 months (49% vs. 24%; P=0.009) favoured rituximab. At 18 months, when B cells were reconstituted in most rituximab-treated patients, the advantage of rituximab (37% vs. 20%; P=0.06) was only a trend.

However, both Dr. Niles and Dr. Jayne suggested that treatment selection in patients with severe disease must be performed on a case-by-case basis. While Dr. Niles identified steroids as the cornerstone of initial treatment, recommending high doses in suspected cases even in advance of a definitive diagnosis, the decision to also employ cyclophosphamide, rituximab, plasma exchange, or all three requires individualization based primarily on expected tolerability. The rationale for using several agents is the potential to block multiple steps in the pathophysiology cascade to achieve more complete and rapid disease control. According to Dr. Niles, cyclophosphamide, like steroids, acts quickly, but the elimination of B cells with rituximab may act on a more fundamental step in the disease process.

Acute Disease Control Critical

“The game is often lost very early in this disease process,” reported Dr. Niles, who considers an “upfront boost” of plasma exchange in life-threatening ANCA vasculitis whether cyclophosphamide, rituximab, or both have already been used. While the combination of rituximab plus cyclophosphamide has not been well studied, he suggested a short and early “bridging” course of cyclophosphamide makes theoretical sense in patients receiving an induction of rituximab and steroids.

“Rituximab is very effective in ANCA vasculitis, but it clears B cells only. It does not clear plasma cells, ANCA, or immediately modify other steps in the cascade,” said Dr. Niles, indicating that its relative strengths may be better for long-term disease control. This observation is at least partially supported by its efficacy in relapsed patients.

Despite advances in defining the causes and molecular pathways of ANCA vasculitis, there are many characteristics that remain perplexing, including the clinical value of considering the major subtypes, such as the granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) forms, when considering the treatment approach. While Dr. Jayne noted that genetic mutations associated with GPA and MPA differ as do some aspects of disease expression, such as dominant histological characteristics, there is limited evidence for employing different therapeutic approaches. He also suggested that many therapies for ANCA vasculitis, including plasma exchange, for which the role is “still not fully defined,” continue to be used on empirical basis.

Retrospective Analysis of Plasma Exchange

Among challenges for trial design in ANCA vasculitis is that it often occurs in the context of a complex set of other serious health issues, such as infection. This complicates efforts to conduct or interpret randomized trials. Much of the treatment data is derived from retrospective analyses. One such analysis, presented at Kidney Week, was derived from the experience at the Massachusetts General Hospital (MGH). This involved all patients with ANCA vasculitis who received plasma exchange over a period of almost 10 years. Most also received cyclophosphamide, corticosteroids and rituximab induction. Overall, results were favourable.

“Of the 70 patients, 41 developed acute kidney injury but escaped the need for dialysis. Of the 29 who did require dialysis during initial hospitalization, 13 recovered renal function,” according to Dr. Charles T. Owens, who presented on behalf of the Joint Nephrology Fellowship Program at MGH. He characterized this study as “one of the largest single-center reports of its kind.” Future analyses will be focused on determining which patients most benefit from plasma exchange.


ANCA vasculitis remains a challenging and complex disease for which individualization of therapy remains important even after considering acute disease severity. Adequate early inhibition of the B cell-initiated inflammatory cascade is essential to reduce injury to the kidney and other susceptible organs, but the therapeutic window is narrow in immunocompromised patients at risk for serious infections. The standard therapy of steroids and cyclophosphamide for mild to moderate disease has not changed, but there is increasing evidence that adding or substituting therapies that inhibit multiple factors in the cascade driving vasculitis will improve induction strategies to prevent the risk of death and the rapidly evolving and irreversible tissue damage which is most common at early stages in the disease process.   

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