Microscopic Polyangiitis

MPA was initially considered as a microscopic form of polyarteritis nodosa. In 1990, the American College of Rheumatology developed classification criteria for several types of systemic vasculitis but did not distinguish between polyarteritis nodosa and microscopic polyarteritis nodosa.[4]

In 1994, a group of experts held an international consensus conference in Chapel Hill, North Carolina, to attempt to redefine the classification of small-vessel vasculitides.[5, 6] A second International Chapel Hill Consensus Conference was held in 2012.[7] The conference recommended categorizing small-vessel vasculitis as follows:

• ANCA-associated vasculitis (AAV) - MPA, GPA, EGPA
• Immune complex–associated small-vessel vasculitis - Anti-glomerular basement membrane (anti-GBM) disease, cryoglobulinemic vasculitis, IgA vasculitis (Henoch-Schönlein), hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)

In addition, the conference recommended adding the following categories of vasculitis:

• Variable vessel vasculitis - Behcet disease, Cogan syndrome
• Single-organ vasculitis (eg, cutaneous leukocytoclastic angiitis, isolated aortitis)
• Vasculitis associated with systemic disease (eg, lupus, rheumatoid arthritis, sarcoid)
• Vasculitis associated with probable etiology (eg, hepatitis, drugs, cancer)

Classification criteria

The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) have published classification criteria for MPA. The criteria are intended tobe used for enrolling patients in studies, not for clinical diagnosis. The classification criteria should be applied after a diagnosis of small- or medium-vessel vasculitis has been made, and alternative disorders mimicking vasculitis have been excluded.[8]

Criteria and assigned scores are as follows[8] :

• Positive test for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) or antimyeloperoxidase (anti-MPO) antibodies: +6
• Pauci-immune glomerulonephritis: +3
• Lung fibrosis or interstitial lung disease: +3
• Sino-nasal symptoms or signs: -3
• Positive test for cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) or antiproteinase 3 (anti-PR3) antibodies: -1
• Blood eosinophil count ≥ 1 × 10  ⁹/L: -4

For the purposes of classification, a patient with a total score of 5 or more is said to have MPA. These criteria have a sensitivity of 91% and a specificity of 94%.[8]

Vasculitis is inflammation of the vessel walls. This may lead to necrosis and bleeding. MPA is characterized by pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of granulomatous inflammation.

Based on current understanding of the inflammatory response, cytokine-mediated changes in the expression and function of adhesion molecules coupled with inappropriate activation of leukocytes and endothelial cells are postulated to be the primary factors influencing the degree and location of vessel damage in the vasculitis syndromes. However, the stimuli that initiate these pathologic inflammatory changes are not well understood.

ANCA may play a role in the pathogenesis of MPA.

Case reports have described an association of MPA with medications (eg, propylthiouracil, hydralazine, rifampicin, ethambutol) and with diseases such as primary biliary cirrhosis.[9, 10, 11]

With the increased availability of ANCA testing, reported cases of MPA have also risen. A 20-year population-based study in Rochester, Minnesota estimated the incidence of MPA at 1.6 per 100,000 persons.[12]

Internationally, the incidence is approximately two cases per 100,000 persons in the United Kingdom. In Sweden and Germany, the incidence is estimated to be 1.3 per 100,000 persons.[13, 14]

The median age of onset is approximately 50 years. MPA is more common in White persons than Black persons; males are affected slightly more frequently than females.

With treatment, 90% of patients with MPA improve and 75% achieve complete remission. The 5-year survival rate is approximately 75%. MPA carries a worse long-term survival rate than granulomatosis with polyangiitis (GPA) or Churg-Strauss syndrome, probably because of kidney involvement at disease onset.

Of patients with MPA, 30% relapse in 1-2 years. Oh et al reported that neither myeloperoxidase (MPO)-ANCA nor proteinase 3 (PR3)-ANCA positivity at diagnosis affected prognosis. However, risk of relapse was significantly higher in patients with chest and renal manifestations, Birmingham vasculitis activity score  ≥13.5, or five factor score ≥1.[15]

Long-term damage in a study of 296 patients with MPA or GPA, as measured with the Vasculitis Damage Index (VDI), was associated with the severity of initial disease, older age, the number of relapses, and duration of glucocorticoid treatment. Patients were followed for 7 years post-diagnosis. Mean duration of glucocorticoid treatment was 40.4 months.[16]

In another study of 151 patients with ANCA-associated vasculitis, patients presenting with pulmonary involvement at baseline had higher damage and disease activity scores at 6, 12 and 24 months follow-up. Patients presenting with lung involvement had an increased risk of developing cardiovascular and kidney involvement and were more likely to develop pulmonary fibrosis.[17]

Complications of vasculitis depend on the particular organ system involvement (see Physical). One of the most significant complications of treatment is bladder cancer. Of patients treated with cyclophosphamide, 5% develop bladder cancer after 10 years and 16% develop bladder cancer after 15 years.

One study reviewed cardiovascular outcomes during long-term follow-up of patients with MPA and GPA in the first 4 European Vasculitis Study Group trials. A model was developed and validated to predict those at risk for a cardiovascular event. Older age, diastolic hypertension, and positive PR3-ANCA status were found to be independent determinants of cardiovascular outcomes. Within 5 years of diagnosis, 14% of patients experienced a cardiovascular event.[18]

The French Vasculitis Study Group Relapse Score (FRS) was developed to predict the probability of relapse in patients with MPA or GPA.[19] The FRS assigns each of the following features 1 point:

•  PR3-ANCA positivity
• Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m²
• Age ≤75 years

In the validation cohort, the FRS score and associated 5-year relapse risk was as follows:

• FRS 0: 8%
• FRS 1: 30%
• FRS 2: 48%
• FRS 3: 76%

Patients with MPA should be aware of the severity of the disease and the risk of recurrence. Compliance with medications and follow-up visits is critical.

Constitutional manifestations of microscopic polyangiitis (MPA) include the following:

• Fever (55%)
• Malaise, fatigue, flulike syndrome
• Myalgia (48%)
• Weight loss (72%)

Renal manifestations are seen in more than 80% of patients and fall on a spectrum from asymptomatic hematuria to necrotizing crescentic GN causing end-stage kidney disease[20] . 

Other manifestations of MPA include the following:

• Skin - Rash (50%)
• Pulmonary - Hemoptysis (11%), dyspnea, cough
• Cardiovascular – Chest pain, symptoms of heart failure
• Gastrointestinal (GI) - GI bleeding, abdominal pain
• Neurologic - Peripheral nervous system involvement manifesting as mononeuritis multiplex (57%); CNS involvement manifesting as seizures (11%)
• Arthralgias (10-50%)
• Testicular pain (2%)
• Ocular (1%) - Red eye, ocular pain, decreased visual acuity
• Symptoms of sinusitis (1%)

The physical examination findings include fever and the manifestations of specific organ system involvement. A dermato-pulmonary-renal syndrome is the feature of the disease.

Skin findings are as follows:

• Leukocytoclastic angiitis and its palpable purpura  - Leukocytoclastic purpura could be a manifestation of the systemic vasculitides or could be a stand-alone skin disorder (see image below.)

  Leukocytoclastic angiitis.
• Palpable purpura (41%)
• Livedo reticularis (12%)
• Skin ulcerations
• Necrosis and gangrene
• Necrotizing nodules
• Digital ischemia (7%)
• Urticaria - Vasculitis-associated urticaria that lasts longer than 24 hours

Compared to GPA and EGPA, MPA is more closely associated with livedoid changes, and vascular inflammation tends to be deeper in the skin; extravascular granulomas are not present.[21]

Respiratory findings in the lower respiratory system include pulmonary rales and respiratory distress. In the upper respiratory tract, sinusitis is less frequent than in granulomatosis with polyangiitis (Wegener granulomatosis).

Cardiovascular findings include the following:

• Hypertension (34%)
• Signs of heart failure (17%)
• Myocardial infarction (2%)
• Pericarditis (10%)

Gastrointestinal findings include the following:

• Gastrointestinal bleeding
• Bowel ischemia and perforation
• Pancreatitis

Ocular findings (1%) include the following:

• Retinal hemorrhage
• Scleritis
• Uveitis

Renal findings comprise signs of uremia in advanced renal failure; 8% of patients with MPA present with renal failure and require hemodialysis. 

Musculoskeletal findings include synovitis and arthritis.

Neurologic findings are as follows:

• Mononeuritis multiplex - Most frequent neurologic manifestation of the disease (57%)
• CNS involvement - Includes meningeal vasculitis (11%)

Orchitis is present in 2% of male patients.

The complete blood cell count (CBC) in patients with microscopic polyangiitis (MPA) demonstrates leukocytosis and a normocytic anemia. The erythrocyte sedimentation rate (ESR) is elevated.

Kidney function test results are as follows:

• Elevated blood urea nitrogen (BUN) and serum creatinine levels (70%)
• Abnormal urine sediment
• Proteinuria (80%)
• Hematuria (67%)
• Leukocyturia (44%)
• Erythrocyte casts

Antineutrophil cytoplasmic antibody (ANCA) test results are as follows:

• ANCA positive (80%)
• Perinuclear ANCA related to myeloperoxidase ANCA (60%)
• Cytoplasmic ANCA related to proteinase-3 ANCA (40%)

Blood cultures may be performed to rule out bacterial endocarditis. On complement testing, C3 and C4 levels are normal.

Chest radiograph findings are as follows:

• Bilateral irregular, nodular, and patchy opacities
• Pulmonary cavitary lesions (less frequently than in granulomatosis with polyangiitis [Wegener granulomatosis])
• Diffuse parenchymal infiltrates secondary to pulmonary alveolar capillaritis and hemorrhage (see image below)

Pulmonary alveolar capillaritis.

Other imaging studies may be indicated for the complications of the disease and specific organ system involvement. For example, abdominal computed tomography may be indicated for suspected pancreatitis, or mesenteric angiography to differentiate MPA from polyarteritis nodosa.

Other tests may be ordered according to the specific organ system involved, as follows:

• Electrocardiography (ECG) - For possible myocardial infarction, pericarditis, or heart failure
• Gastrointestinal endoscopy - In cases of gastrointestinal bleeding
• Electromyography (EMG) - In patients with clinical evidence of neuropathy

Biopsy

The following biopsies may be useful:

• Skin biopsy if skin is involved
• Open lung biopsy
• Renal biopsy to help diagnose crescentic glomerulonephritis
• Sural nerve biopsy if EMG results are consistent with sural nerve involvement

The results of a retrospective study suggest muscle biopsy may be helpful for the diagnosis of systemic vasculitides even in the absence of myalgias or creatine phosphokinase (CPK) elevation.[22]

Pathologically, microscopic polyangiitis (MPA) may cause necrotizing arteritis that is histologically identical to that caused by polyarteritis nodosa.

According to the Chapel Hill consensus conference on the classification of small vessel vasculitis, polyarteritis nodosa and MPA are distinguished pathologically by the absence of vasculitis in vessels other than arteries in patients with polyarteritis nodosa and the presence of vasculitis in vessels smaller than arteries, such as arterioles, venules, and capillaries, in patients with MPA.

Because of sparing of muscular and larger vessels in MPA, macroscopic infarcts similar to those seen in polyarteritis nodosa are uncommon. Histologically, segmental fibrinoid necrosis of the media may be present, but in some, the change is limited to infiltration with neutrophils, which become fragmented as they follow the vessel wall (leukocytoclasia). The term leukocytoclastic angiitis is given to such lesions, most commonly found in postcapillary venules.

Immunoglobulins and complement components may be present in the vascular lesions of the skin. The paucity of immunoglobulin is demonstrable using immunofluorescence microscopy (ie, pauci-immune injury).

The glomerulonephritis in MPA is characterized by focal necrosis, crescent formation, and the absence or paucity of immunoglobulin deposits. Pulmonary manifestation is in the form of pulmonary alveolar capillaritis. Biopsy of the muscle and sural nerve may reveal necrotizing vasculitis in small and medium vessels.

Histopathology of alveolar hemorrhage in alveolar capillaritis.

Crescentic glomerulonephritis.

Focal segmental glomerulonephritis.

Histopathology of leukocytoclastic angiitis.

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 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. 

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:

• The use of trimethoprim-sulfamethoxazole (TMP-SMX) is controversial in the prevention of relapse. TMP-SMX has shown promising results in patients with GPA. ^{[41, 42]} The relationship between Staphylococcus aureus colonization and the relapse rate has shown a debatable correlation.
• The use of mycophenolate mofetil in the treatment of MPA has been limited. In several small studies, mycophenolate mofetil was effective in maintaining remission in patients with MPA, even in those with moderate-to-severe renal impairment. ^{[43, 44, 45]}
• The use of low-dose cyclosporine for maintenance therapy has been reported ^[46]
• Pneumocystis jiroveci prophylaxis with low-dose TMP-SMX (one double-strength tablet three times weekly) is prudent. ^[45]

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:

• 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
• Nephrologist for help with the diagnosis and management of kidney involvement and possible need for dialysis
• Gastroenterologist, if necessary, for the management of gastrointestinal bleeding
• Surgeon in cases involving catastrophic events in gastrointestinal or other organ systems
• Hematologist if plasmapheresis is considered

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]

Various immunosuppressive agents are used in the treatment of microscopic polyangiitis (MPA). The choice of agents depends on the treatment phase (induction versus maintenance of remission) and disease severity.

Class Summary

First line of treatment for induction of remission and usually for maintenance. For induction of remission, use IV methylprednisolone. For maintenance, use prednisone.

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Steroids ameliorate effects immune reactions and may limit biphasic anaphylaxis.

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Class Summary

These agents inhibit immune reactions that result from diverse stimuli.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards.

As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Rituximab (Rituxan)

Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B-lymphocytes. It is indicated in combination with glucocorticoids for treatment of adult and pediatric patients aged 2 years or older with granulomatosis with polyangiitis (GPA; Wegener granulomatosis) or microscopic polyangiitis (MPA).

Methotrexate (Folex PFS, Rheumatrex)

Should not be used if serum creatinine clearance is >2.0 mg/dL.

Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response. An alternative form of less toxic therapy only for localized and nonaggressive disease is combination of MTX and prednisone.

Azathioprine (Imuran)

Immunosuppressive agent; antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Avacopan (Tavneos)

Complement 5a receptor (C5aR) antagonist that inhibits the interaction between C5aR and the anaphylatoxin C5a. Indicated as adjunctive treatment of severe active antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with glucocorticoids.