Approach Considerations
Treatment of microscopic polyangiitis (MPA) is principally with corticosteroids and other immunosuppressive agents and consists of induction and maintenance of remission.The treatment of relapsed MPA is the same as that of remission induction. Intravenous immunoglobulin has been used in treatment of refractory disease. [23]
MPA can manifest as a mild systemic vasculitis with mild kidney insufficiency, or it can manifest as a full-blown acute disease with rapid deterioration of kidney function and respiratory failure due to pulmonary capillaritis. The choice of medication depends in part on the extent of disease, the rate of progression, and the degree of inflammation.
Induction of Remission
Induction of remission in MPA is customarily achieved with cyclophosphamide and prednisone; glucocorticoid monotherapy is not recommended because of lower remission rates. Cyclophosphamide is started at 1.5-2 mg/kg/d. The patient should be monitored for leukocytopenia and neutropenia. Prednisone is started at 1 mg/kg/d and is continued for 1 month. If significant improvement is seen, the prednisone dose is decreased by 5 mg/wk. Once the dosage of 10 mg/d is reached, the next taper can be to 10 mg every other day. After complete remission, the maintenance phase is started.
In the PEXIVAS trial, which compared two regimens of oral glucocorticoids in patients with severe MPA or granulomatosis with polyangiitis (Wegener granulomatosis; GPA) a reduced-dose regimen proved noninferior to a standard-dose regimen with respect to the risk of death or end-stage kidney disease, and resulted in a lower risk of serious infections in the first year of treatment. The reduced-dose regimen in PEXIVAS provides approximately 55% of the standard-dose regimen over the first 6 months. [24] American College of Rheumatology/Vasculitis Foundation guidelines conditionally recommend a reduced-dose glucocorticoid regimen over a standard-dose regimen for remission induction in MPA and GPA. [25]
The European Vasculitis Study Group reported that in the first year of therapy for ANCA-associated vasculitis (AAV), 59% of deaths were due to therapy-associated adverse events (eg, leukopenia, infection). [26] The risk of adverse effects has prompted a search for alternatives to glucocorticoids.
The the C5a receptor inhibitor avacopan was developed for treatment of AAV. The randomized, controlled ADVOCATE trial compared avacopan with prednisone (both given in combination with either cyclophosphamide, followed by azathioprine, or rituximab) in 331 patients with AAV, and found that avacopan was noninferior to prednisone at week 24 and superior at week 52 for achieving complete remission. [27] Avacopan is approved by the US Food and Drug Administration (FDA) for adjunctive treatment of severe MPA and GPA, in combination with glucocorticoids, and the European Alliance of Associations for Rheumatology (EULAR) suggests considering avacopan as part of a strategy to reduce exposure to glucocorticoids in such patients. [28]
Avacopan is not approved as a substitute for steroids. However, in a small retrospective study by Gabilan et al of patients with de novo or relapsing AAV who presented with rapidly progressive glomerulonephritis, treatment with avacopan plus rituximab led to a high rate of AAV remission, with rapid control of kidney inflammation; glucocorticoids were either stopped or tapered rapidly in these patients. [29]
Other regimens that have been studied for remission induction in MPA include mycophenolate mofetil versus cyclophosphamide and intravenous immunoglobulin in refractory cases. [30] In cases involving life-threatening alveolar capillaritis with pulmonary alveolar hemorrhage, plasmapheresis in addition to intravenous cyclophosphamide and pulse doses of steroids may be used.
For induction of remission in patients with milder manifestations of MPA, a combination of methotrexate and prednisone can be used. However, a significantly higher relapse rate was observed with this combination than with the combination of cyclophosphamide and prednisone. [31] Nevertheless, given the value of limiting the duration of exposure to cyclophosphamide, this regimen offers the advantage of methotrexate's superior safety profile, compared with that of cyclophosphamide, and (because the higher rate of relapse in that study occurred after treatment discontinuation) the likelihood that longer duration of maintenance therapy will result in lower relapse rates. [32]
In 2011, the US Food and Drug Administration (FDA) approved rituximab to treat MPA and GPA. The safety and effectiveness of rituximab was demonstrated in a single controlled trial by the RAVE-ITN Research Group, in which 197 adults with MPA or GPA were randomly assigned to receive either rituximab (375 mg/m2/wk for 4 wk) plus daily prednisone, or cyclophosphamide (2 mg/kg/d) orally plus daily prednisone to induce remission. [33] Prednisone was tapered off. The primary endpoint was remission of disease without use of prednisone at 6 months. After 6 months, 64% of patients treated with rituximab had complete remission compared with 53% of those treated with cyclophosphamide. In 2019, the indication was expanded to include children aged 2 years or older.
Maintenance of Remission
For remission maintenance, the preference is to replace cyclophosphamide, which has high toxicity, with either methotrexate or azathioprine. [34, 35] However, if the serum creatinine concentration is greater than 2 mg/dL, methotrexate is not an option. At this phase, prednisone is continued and cyclophosphamide is replaced with azathioprine at 2 mg/kg/d for 12 months. After a year, the dose of azathioprine is decreased to 1.5 mg/kg/d. If methotrexate is used for maintenance treatment, it can be started at 0.3 mg/kg once a week, with the maximum dose of 15 mg/wk. This is increased by 2.5 mg/wk (maximum 20 mg/wk).
This phase is continued for 12-24 months. Prednisone can be continued at 10 mg/d or every other day.
Analysis of long-term outcomes in 112 patients enrolled in the WEGENT trial confirmed that methotrexate or azathioprine are comparable treatment options for maintaining remission of MPA. The 10-year overall survival rates were 75.1% in patients receiving azathioprine and 79.9% in those receiving methotrexate (P = 0.56), while relapse-free survival rates were 26.3% and 33.5% (P = 0.29), respectively. [36]
A followup study by the RAVE-ITN Research Group demonstrated that a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for inducing and maintaining remission for 18 months. At 18 months, 39% of the patients in the rituximab group had maintained complete remissions, compared with 33% of the patients who received cyclophosphamide for 3 to 6 months followed by azathioprine for 12 to 15 months. [37]
The French Vasculitis Study Group reported that rituximab was more effective than azathioprine for maintaining remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. In this study, 115 patients with newly diagnosed or relapsing GPA, MPA, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. At month 28, 17 patients (29%) in the azathioprine group had experienced major relapse, compared with three patients (5%) in the rituximab group (hazard ratio for relapse, 6.61; P = 0.002).17 On continued follow-up to 60 months, major relapse-free survival rates were 71.9% with rituximab versus 49.4% with azathioprine (P=0.003); overall survival rates were 100% with rituximab versus 93.0% with azathioprine (P=0.045). [38]
Another French Vasculitis Study Group trial compared fixed-schedule and individually tailored rituximab regimens for maintaining remission of ANCA-associated vasculitis, and found that relapse rates did not differ significantly between the two approaches, while patients on individually tailored regimens received fewer rituximab infusions. Patients on individually tailored regimens received an initial 500-mg rituximab infusion and then underwent testing every 3 months, with rituximab reinfusion only when CD19+ B lymphocytes or ANCA had reappeared or the ANCA titer rose markedly. [39]
The long-term safety of rituximab in MPA was documented in a phase IV, open-label, prospective 4-year observational registry of adult patients with MPA or GPA. The safety profile of rituximab proved consistent with that of shorter-term treatment and with rituximab's known safety profile in other autoimmune diseases. [40]
Other therapies include the following:
Consultations
A rheumatologist would be the main consultant who helps with the diagnosis and immunosuppressive therapy. Additional consultations would be based on the specific organ system involvement, as follows:
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Pulmonologist for the management of hemoptysis due to pulmonary alveolar capillaritis; additionally, consult a pulmonologist to help with the management of respiratory failure associated with diffuse alveolar hemorrhage and with the diagnosis of pulmonary involvement
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Nephrologist for help with the diagnosis and management of kidney involvement and possible need for dialysis
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Gastroenterologist, if necessary, for the management of gastrointestinal bleeding
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Surgeon in cases involving catastrophic events in gastrointestinal or other organ systems
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Hematologist if plasmapheresis is considered
Long-Term Monitoring
Patients with microscopic polyangiitis (MPA) need to be monitored very closely at a rheumatology clinic. Patients need to take immunosuppressive medications for a long time, at least for a year. Clinical status and the erythrocyte sedimentation rate (ESR) should be monitored.
The level of ANCA may be used to monitor disease activity. However, ANCA levels do not correlate consistently with the disease activity. In one study, ANCA levels became undetectable in 83% of patients after treatment; however, ANCA levels increased in 57% of patients at a mean period of 7.8 weeks prior to relapse. Reappearance of anti-MPO antibodies has positive predictive value for relapse. [47, 48]
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Pulmonary alveolar capillaritis.
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Histopathology of alveolar hemorrhage in alveolar capillaritis.
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Crescentic glomerulonephritis.
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Focal segmental glomerulonephritis.
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Histopathology of leukocytoclastic angiitis.
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Leukocytoclastic angiitis.
