What is ANCA Vasculitis?

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an uncommon inflammatory disease of small to medium-sized vessels that frequently presents with rapidly progressive glomerulonephritis and renal failure. However, it can affect any organ system.

AV occurs when neutrophils attack small and medium vessels of the body; the underlying reason for this remains unclear. The clinical signs vary and affect several organs, such as the kidney, stomach, intestine, and lung. Skin lesions, such as purpura and urticaria, result when blood from small vessels leaks under the skin.

There are three subtypes of the disease, i.e., granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA, formerly Churg-Strauss syndrome). In the absence of a known cause, the vasculitides are first classified according to the size of the vessels that are predominantly involved.

AAV predominantly affects small vessels, defined as small intraparenchymal arteries, arterioles, capillaries, and venules. Distinguishing between the different forms of AAV, particularly GPA and MPA, has been a longstanding problem for clinicians and researchers alike. There are, however, many epidemiological and genetic studies suggesting that GPA and MPA are two distinct pathological processes, which could warrant different treatment modalities in the future.

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It has been observed that MPA, which is more commonly positive for myeloperoxidase (MPO)-ANCA and a perinuclear staining pattern (p-ANCA), was the predominant subtype in Japan. In contrast, GPA, which is more commonly positive for PR3-ANCA and a cytoplasmic staining pattern (c-ANCA), was the predominant subtype in the UK.

In European studies, the ANCA antigen specificity of GPA is most frequently associated with PR3, while the specificity of MPA is more commonly associated with MPO. If untreated, the vast majority of patients can die within a year. Current treatments improve prognosis, but affected patients remain at a substantially higher risk of death and adverse outcomes.

Since the discovery of anti-neutrophil cytoplasmic antibodies (ANCA) in 1982, enormous progress has been made in the understanding of the associated diseases and their treatment. From a diagnostic viewpoint, the elucidation of proteinase 3 (PR3) and myeloperoxidase (MPO) as the relevant antigenic specificities of ANCA in the ANCA-associated vasculitis (AAV) has strongly improved early diagnosis and treatment of these diseases.

Treatment of AAV follows type- and activity-adapted regimens according to evidence from controlled trials which have been summarized in the EULAR (European League against Rheumatism) recommendations published in 2009.

In general, a period of remission induction using highly-potent immunosuppression (e.g. with cyclophosphamide, Cyc plus glucocorticoids, GC) for 3–4 months is followed by maintenance therapy (e.g. azathioprine plus low-dose GC) which is supposed to be kept for at least 1.5–2 years. Induction therapy with a combination of high-dose steroids and cyclophosphamide has been the standard therapy for over 30 years and greatly improves survival among patients with AAV. Current research is focused on improving efficacy and reducing side effects of the medications used to induce remission.

For EGPA, the current approach to disease management is primarily based on reduction of active inflammation and suppression of the immune response through the use of corticosteroids and concomitant immunosuppressive therapy (e.g., methotrexate, azathioprine, and mycophenolate mofetil) and/or cytotoxic agents (e.g. cyclophosphamide). Although the use of these treatments can be effective for establishing remission, patients remain vulnerable to either the complications of the long-term use of these therapies and to the risk of relapse, particularly if the dose of corticosteroid is reduced.

One large randomized noninferiority trial of patients with AAV has found Rituximab (RTX) to be noninferior to cyclophosphamide as induction therapy, including among the patients with renal involvement at enrollment. A randomized controlled trial comparing the effectiveness of daily oral cyclophosphamide versus intravenous pulses suggested that the pulse regimen significantly reduced cumulative exposure and was not associated with any significant difference in time to remission.

Other agents, including tacrolimus, intravenous immunoglobulin (IVIG) and anti-TNF-α compounds such as etanercept and infliximab, have previously been explored in the treatment of AAV, however, the current evidence supporting their use is limited and, in light of the demonstrable efficacy of other agents, are unlikely to be adopted as first-line induction therapy. Nevertheless, there are relatively few trials that have explored the efficacy of these agents in combination therapy.

Azathioprine (AZA) was established as the drug of choice for maintenance therapy in the trial which found introducing AZA within 3 months of inducing clinical remission did not result in more early relapses than continuing cyclophosphamide for 12 months. The role of AZA as the preferred agent for maintenance therapy was reinforced by head to head trials comparing AZA to mycophenolate mofetil (MMF) and methotrexate which did not find evidence to support the use of these alternative agents. Indeed, AZA was associated with fewer relapses compared to MMF without a significant difference in serious adverse event rates.

There is a lack of evidence to guide treatment decision in localized disease. Cotrimoxazole may be used for remission induction in upper airway disease in WG; however, in patients with persistent, localized WG, medium- to highly-potent immunosuppression seems required as cotrimoxazole was not sufficient to control disease activity in a significant proportion of patients. Methotrexate (MTX) has been shown to be effective in inducing remission in GPA/MPA with a non-organ threatening disease (early systemic disease) in several trials including one controlled trial (NORAM, non-renal alternative treatment with MTX).

Apart from these medicines, In December 2017, the US Food and Drug Administration (FDA) has approved Nucala (mepolizumab) as the first targeted treatment for eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome. In September 2019, Genentech announced that the US FDA approved Rituxan (rituximab), in combination with glucocorticoids, for the treatment of GPA and MPA in pediatric patients 2 years of age and older.

Treatment of AAV has evolved, and with currently available immunosuppressive therapy, up to 85–90% of patients will achieve remission. Tailored therapy that circumvents most of the toxicity associated with care should be the goal. In addition to disease-specific therapy, key management concepts for all patients include prophylaxis and monitoring for conditions (infections).