Paradigm shift in the management of ANCA-associated vasculitis

Pathogenetic concepts lead to targeted therapy

Three systemic autoimmune small vessel vasculitis syndromes are associated with antineutrophil cytoplasmic autoantibodies (ANCAs); collectively, they're called ANCA-associated vasculitis (AAV). AAV include:

  • Microscopic polyangiitis (MPA)
  • Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis
  • Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome

The respiratory system is commonly involved in all three syndromes, which share certain histopathologic and clinical features. Other features are unique and disease-defining.

Diffuse alveolar hemorrhage is a potentially life-threatening complication of each of these syndromes. Patients with diffuse alveolar hemorrhage often require ICU care. Caused by pulmonary capillaritis, diffuse alveolar hemorrhage affects 20 to 30 percent of patients with MPA and GPA, but less than 5 percent of patients with EGPA. Other clinical manifestations caused by necrotizing small vessel vasculitis and capillaritis, such as glomerulonephritis, palpable purpura, scleritis, or sensory and motor mononeuropathies, also can occur in all three syndromes.

Granulomatous inflammation, which predominantly affects the respiratory tract, causes characteristic clinical features setting GPA and EGPA apart from MPA. The granulomatous inflammation is necrotizing and neutrophilic in GPA, but eosinophilic in EGPA. The necrotizing granulomatous inflammation of GPA can cause pulmonary nodules or mass lesions and affect the large airways leading to subglottic and endobronchial stenoses. Asthma and peripheral blood eosinophilia, the defining characteristics of EGPA, are not features of GPA or MPA.

The type of ANCA also seems to affect the disease phenotype of ANCA-associated vasculitis. Two types of ANCAs are of clinical significance in patients with vasculitis:

  • ANCAs causing a cytoplasmic immunofluorescence pattern (C-ANCAs) on ethanol-fixed neutrophils that react with proteinase 3 (PR3-ANCAs)
  • ANCAs causing a perinuclear immunofluorescence pattern (P-ANCAs) on ethanol-fixed neutrophils that react with myeloperoxidase (MPO-ANCAs)

PR3-ANCAs occur in the vast majority of patients with GPA, while MPO-ANCAs occur far less frequently. In contrast, MPO-ANCAs are the predominant type of ANCAs in patients with both MPA and EGPA.

Recent advances in pathogenesis

Significant progress has been made over the last two decades in understanding the pathogenesis of AAV. Research conducted at Mayo Clinic and elsewhere has paved the way for novel and individually targeted therapeutic approaches. Clinical and experimental evidence supports the concept that a genetic predisposition for autoimmunity, epigenetic factors and environmental triggers are necessary for the loss of tolerance and development of an inflammatory milieu that supports the production of ANCAs. In the context of an inflammatory milieu, ANCAs can cause specific tissue inflammation and vascular injury by a variety of different mechanisms that involve direct interactions with the respective ANCAs' target antigens PR3 or MPO.

A genome-wide association study found major histocompatibility complex (MHC) and non-MHC associations with AAV and genetic distinctions between GPA and MPO, and even more clearly between PR3- and MPO-ANCA-associated diseases, providing support for the concept that they are genetically distinct autoimmune disorders. The documented higher relapse rate of patients with PR3-ANCAs compared with MPO-ANCAs may have a genetic basis.

A large body of experimental work supports that B lymphocytes are essential for the development of ANCAs and disease activity, whereas T lymphocyte abnormalities seem to persist, particularly in patients with GPA, even during remission. The presence of ANCAs alone does not inevitably cause disease, but ANCAs seem necessary for the development of disease manifestations caused by capillaritis, such as alveolar hemorrhage, glomerulonephritis, scleritis or mononeuritis multiplex.

For all of these reasons, interventions aimed at B lymphocytes, T lymphocytes and ANCA have made inroads into the therapeutic arsenal for AAV.

Recent advances in therapy

About four decades ago, the introduction of cyclophosphamide (Cytoxan) changed the invariably fatal outcome of severe GPA and MPA. Remission could be successfully induced with the combination of glucocorticoids and cyclophosphamide, and the syndromes became manageable chronic conditions. Unfortunately, the relapsing nature of GPA and MPA often requires repeated and sometimes prolonged exposure to cyclophosphamide, causing significant cumulative toxicity. Infertility in both women and men is induced after only a few months of exposure, and solid as well as hematologic malignancies are dreaded late complications of cyclophosphamide exposure. Moreover, some patients could not achieve stable remission with maximal tolerated cyclophosphamide doses.

For these reasons, better tolerated alternatives were desperately needed. Randomized controlled trials and prospective observational cohort studies first showed that methotrexate could replace cyclophosphamide in patients with limited or nonsevere disease GPA. For patients with MPA and mild renal disease, mycophenolate mofetil (CellCept) might be the alternative.

Biologic response modifiers allowing mechanism-based treatment approaches have become available over the last decade. Targeting specific molecules, these agents can block immune pathways thought to cause maladaptive inflammation in autoimmune diseases by inhibiting pro-inflammatory cytokines, eliminating cells of defined lineage (B lymphocytes) or inhibiting their activation or recruitment (T lymphocytes, eosinophils).

The ability to specifically target B lymphocytes with rituximab (Rituxan), a chimeric monoclonal antibody against the B lymphocyte specific cell surface receptor CD20, has fundamentally changed the therapy of severe AAV. Following the first report of its use in AAV in 2001, experience with rituximab in AAV has rapidly expanded. The Rituximab Versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial showed that rituximab was not inferior to cyclophosphamide for remission induction in severe GPA and MPA. In fact, for patients with relapsing disease, rituximab was found to be superior to cyclophosphamide. Based on the primary endpoint results of RAVE, the Food and Drug Administration (FDA) approved rituximab in combination with glucocorticoids for remission induction in newly diagnosed and relapsing severe GPA and MPA.

The 18-month follow-up study of RAVE, led by researchers at Mayo Clinic, showed that a single course of four once-weekly infusions of rituximab is as effective for remission induction and maintenance as 18 months of continuous immunosuppressant therapy with cyclophosphamide followed by azathioprine (Imuran). Long-term single-center cohort studies indicated that rituximab is also effective and safe for remission maintenance, particularly in chronically relapsing GPA. In 2013, most patients with GPA and MPA can be managed without exposure to cyclophosphamide and its dreaded long-term toxicities.

A role for biologic response modifiers is also emerging for EGPA. Glucocorticoids have long been the mainstay of treatment, and cyclophosphamide is used for disease activity that threatens the function of vital organs. Side effects of glucocorticoids represent the biggest challenge in the long-term management of this disease. The exact mechanisms of tissue injury in EGPA remain unclear, but blood and tissue eosinophilia appear to be responsible for tissue damage.

Interleukin-5 (IL-5) mediates bone marrow release, tissue survival, maturation and activation of eosinophils. Furthermore, IL-5 levels are increased in patients with EGPA and are associated with disease activity. Consequently, reducing the number of eosinophils and preventing their activation by inhibiting IL-5 appears to be a rational novel approach for EGPA. Mepolizumab, a monoclonal antibody targeting IL-5, has shown promise in EGPA. Small pilot trials demonstrated prompt and prolonged reduction of peripheral eosinophils, clinical improvement and reduction in glucocorticoid use. A large multicenter randomized controlled trial of this agent in EGPA is underway. Small case series and a pilot trial suggest that rituximab may represent an alternative to cyclophosphamide in severe EGPA, particularly if it's MPO-ANCA-associated.

Multidisciplinary approach to management

At Mayo Clinic, a multidisciplinary team of experts collaborates to provide optimal care to patients with this complex multisystem disorder. This team will often include pulmonologists, nephrologists, rheumatologists, otolaryngologists, neurologists, and sometimes dermatologists or endocrinologists.

The role of otolaryngologists is particularly important for patients with GPA, many of whom suffer from conductive or sensorineural hearing loss, chronic rhinosinusitis, and subglottic stenosis. Surgical interventions to address these disease complications need to be carefully coordinated and appropriately timed in consideration of each patient's status of disease activity. Most surgical procedures aimed at restoring airway patency, such as reconstruction of a saddle nose deformity or dilatation of a subglottic stenosis with intralesional injection of long-acting glucocorticoids and mitomycin C, should be performed when systemic disease activity is well-controlled. Tracheal and bronchial stenoses often benefit from care by interventional bronchoscopists experienced with GPA.

As for the management of subglottic stenosis, dilatation procedures and stent placement decisions need to be individualized and coordinated in the context of overall disease activity control.

Ongoing and imminent clinical trials enrolling patients at Mayo Clinic

Plasma exchange has been advocated for use in patients with severe alveolar hemorrhage leading to respiratory failure and for severe renal disease. The rationale for this approach is that the rapid removal of pathogenic ANCAs might be beneficial in rapidly progressive disease. The data supporting this practice, however, are inconclusive. The FDA and multiple international agencies have joined forces to cooperatively fund an ongoing global randomized trial (PEXIVAS) to evaluate the efficacy and safety of plasma-exchange for patients with ANCA-associated renal disease or diffuse alveolar hemorrhage or both.

The biggest remaining challenge in the management of these relapsing conditions is the long-term maintenance of remission with minimum cumulative drug toxicities. The relapse risk is not the same for all patients. For these reasons, the focus of phase III randomized controlled trials has shifted from remission induction trials to remission maintenance trials.

While rituximab may be effective for remission maintenance in GPA and MPA, the best dosing and timing of re-treatment as well as efficacy and safety of long-term B lymphocyte depletion compared with traditional agents remains to be clarified by larger randomized controlled trials. Currently, an international, open-label, randomized trial comparing rituximab versus azathioprine for maintenance of remission following induction with rituximab in relapsing GPA and MPA patients (RITAZAREM) is open for enrollment.

Other biologic agents may also be of interest for remission maintenance. Belimumab (Benlysta) is a human IgGΛ monoclonal antibody that neutralizes soluble B cell activating factor (BAFF), also called B lymphocyte stimulator (BLyS). BAFF is essential for B lymphocyte development and survival as well as immunoglobulin production. Targeting BAFF with belimumab is effective and safe in systemic lupus erythematosus. As B lymphocytes appear crucial for AAV disease activity, the Belimumab in Remission of Vasculitis (BREVAS) trial is designed to evaluate the efficacy and safety of belimumab in combination with azathioprine for remission maintenance in GPA or MPA following standard remission induction.

Abnormalities of T lymphocyte activation seem to hold the key to chronic relapses in AAV. Full activation of T lymphocytes can be prevented by inhibiting the costimulatory signaling required for full T lymphocyte activation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) down regulates T lymphocyte costimulation under physiologic conditions.

Abatacept (CTLA-4-IgG1) is a recombinant fusion protein consisting of the ligand binding portion of CTLA-4 and a modified Fc portion of human IgG1 that acts therapeutically by blocking T lymphocyte costimulation. This agent is approved for the use in rheumatoid arthritis, and a pilot trial with abatacept in nonsevere GPA has yielded promising results. A phase III study of abatacept (ABROGATE) will clarify the potential role of this agent in the treatment of relapsing, nonsevere GPA.

For more information

Belimumab in remission of vasculitis (BREVAS). ClinicalTrials.gov.

Plasma exchange and glucocorticoids for treatment of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (PEXIVAS). ClinicalTrials.gov.

Rituximab vasculitis maintenance study (RITAZAREM). ClinicalTrials.gov.

Points to remember

  • Treatment for GPA and MPA consists of a multidisciplinary individualized approach based on disease severity and specific organ involvement.
  • Rituximab has emerged as an alternative to cyclophosphamide for most patients and is the preferred agent for severe disease relapses.
  • The different ANCA types, PR3-ANCAs versus MPO-ANCAs, have a different genetic background and portend a different prognosis and risk of relapse.
  • Plasma exchange and biologic agents targeting B lymphocytes and T lymphocyte activation are under investigation for GPA and MPA, and anti-IL-5 therapy targeting eosinophils with mepolizumab is under investigation for EGPA.