Microscopic Polyangiitis 

Updated: Jul 31, 2018
Author: Mehran Farid-Moayer, MD; Chief Editor: Vecihi Batuman, MD, FASN 

Overview

Practice Essentials

Microscopic polyangiitis (MPA) is a vasculitis of small vessels. Patients frequently present with renal manifestations, but systemic manifestations, arthritis, mononeuritis multiplex, and other signs and symptoms are also common.[1]  (See Presentation and Workup.)

Vasculitis in small vessels, including arterioles, capillaries, and venules, a characteristic of MPA, is absent in polyarteritis nodosa. This absence is the proposed distinguishing feature between those two disorders. Granulomatosis with polyangiitis (Wegener granulomatosis, GPA), MPA, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome, EGPA) comprise a category of small vessel vasculitis related to antineutrophil cytoplasmic antibodies (ANCAs) and are characterized by a paucity of immune deposits.

MPA and GPA seem to be part of a clinical spectrum. However, an absence of granuloma formation and sparing of the upper respiratory tract are features of MPA. These features help to distinguish MPA from GPA, although the two conditions are occasionally difficult to distinguish.

The image below depicts pulmonary alveolar capillaritis.

Pulmonary alveolar capillaritis. Pulmonary alveolar capillaritis.

Immunosuppressive medications are used to control MPA. The choice of agents depends in part on the extent of disease, the rate of progression, and the degree of inflammation. See Treatment and Medication.

See Vasculitis: Case Presentations, a Critical Images slideshow, for more information on clinical, histologic, and radiographic imaging findings in various forms of vasculitis.

Background

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.[2]

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.[3, 4] A second International Chapel Hill Consensus Conference was held in 2012.[5] 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)

Pathophysiology

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.

Etiology

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 such as propylthiouracil and with diseases such as primary biliary cirrhosis.[6, 7]

Epidemiology

In the United States, the annual incidence of MPA is 3.6 cases per million persons. The prevalence is one to three cases per 100,000 population.

Internationally, the incidence is approximately two cases per 100,000 persons in the United Kingdom and approximately one case per 100,000 persons in Sweden.

Race-, Sex-, and Age-related Demographics

Demographic features of MPA in the United States are as follows:

  • MPA is more frequent in white persons than black persons

  • Males are affected slightly more frequently than females

  • The median age of onset is approximately 50 years

Prognosis

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 or Churg-Strauss syndrome, probably because of renal 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.[8]

Long-term damage in a study of 296 patients with MPA or granulomatosis with polyangiitis, 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.[9]

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 renal involvement and were more likely to develop pulmonary fibrosis.[10]

 

Presentation

History

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

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

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%)
  • Myalgias (40%)
  • Testicular pain (2%)
  • Ocular (1%) - Red eye, ocular pain, decreased visual acuity
  • Symptoms of sinusitis (1%)

Physical

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. 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

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.

 

DDx

 

Workup

Laboratory Studies

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.

Renal testing 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.

Imaging Studies

Chest radiograph findings are as follows:

  • Bilateral irregular, nodular, and patchy opacities

  • Pulmonary cavitary lesions (less frequently than Wegener granulomatosis)

  • Diffuse parenchymal infiltrates secondary to pulmonary alveolar capillaritis and hemorrhage (see image below)

    Pulmonary alveolar capillaritis. 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

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 cases of clinical evidence of neuropathy

Procedures

See the list below:

  • 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.[11]

Histologic Findings

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 Histopathology of alveolar hemorrhage in alveolar capillaritis.
Crescentic glomerulonephritis. Crescentic glomerulonephritis.
Focal segmental glomerulonephritis. Focal segmental glomerulonephritis.
Histopathology of leukocytoclastic angiitis. Histopathology of leukocytoclastic angiitis.
 

Treatment

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.[12]

MPA can manifest as a mild systemic vasculitis with mild renal insufficiency, or it can manifest as a full-blown acute disease with rapid deterioration of renal 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. 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.

For induction of remission in patient 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.

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.

Glucocorticoid monotherapy is not recommended because of lower remission rates.

In April 2011, the US Food and Drug Administration (FDA) approved rituximab to treat MPA and granulomatosis with polyangiitis (Wegener granulomatosis; 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.[13] 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. 

Maintenance of Remission

For remission maintenance, the preference is to replace cyclophosphamide, which has high toxicity, with either methotrexate or azathioprine.[14, 15] 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 thatmethotrexate 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.[16]

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.[17]

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).[18]

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. [19]

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. [20, 21] 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. [22, 23, 24]
  • The use of low-dose cyclosporine for maintenance therapy has been reported [25]
  • Pneumocystis jiroveci prophylaxis with low-dose TMP-SMX (one double-strength tablet three times weekly) is prudent. [24]

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:

  • Consult a 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

  • Consult a nephrologist for help with the diagnosis and management of renal involvement and possible need for dialysis

  • Consult a gastroenterologist, if necessary, for the management of gastrointestinal bleeding

  • Consult a surgeon in cases involving catastrophic events in gastrointestinal or other organ systems

  • Consult a hematologist if plasmapheresis is considered

 

Medication

Medication Summary

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.

Corticosteroids

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.

Immunosuppressive agents

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.

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.

 

Follow-up

Further Outpatient Care

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.[26, 27]

Complications

See the list below:

  • Complications of vasculitis depend on the particular organ system involvement (see Physical).

  • One of the most significant complications of treatment is bladder cancer. Among people who are 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 granulomatosis with polyangiitis and microscopic polyangiitis 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.[28]

Patient Education

See the list below:

  • 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.

 

Questions & Answers

Overview

What is microscopic polyangiitis (MPA)?

How is microscopic polyangiitis (MPA) categorized?

What is the pathophysiology of microscopic polyangiitis (MPA)?

What causes microscopic polyangiitis (MPA)?

What is the prevalence of microscopic polyangiitis (MPA)?

Which patient groups have the highest prevalence of microscopic polyangiitis (MPA)?

What is the prognosis of microscopic polyangiitis (MPA)?

Presentation

What are the signs and symptoms of microscopic polyangiitis (MPA)?

Which physical findings are characteristic of microscopic polyangiitis (MPA)?

Which dermatologic findings are characteristic of microscopic polyangiitis (MPA)?

Which respiratory findings are characteristic of microscopic polyangiitis (MPA)?

Which cardiovascular findings are characteristic of microscopic polyangiitis (MPA)?

Which GI findings are characteristic of microscopic polyangiitis (MPA)?

Which ocular findings are characteristic of microscopic polyangiitis (MPA)?

Which renal findings are characteristic of microscopic polyangiitis (MPA)?

What are musculoskeletal findings are characteristic of microscopic polyangiitis (MPA)?

Which neurologic findings are characteristic of microscopic polyangiitis (MPA)?

DDX

What are the differential diagnoses for Microscopic Polyangiitis?

Workup

Which complete blood cell count (CBC) findings suggest microscopic polyangiitis (MPA)?

Which findings on renal testing suggest microscopic polyangiitis (MPA)?

Which antineutrophil cytoplasmic antibody (ANCA) test results suggest microscopic polyangiitis (MPA)?

What is the role of blood cultures in the diagnosis of microscopic polyangiitis (MPA)?

Which chest radiograph findings suggest microscopic polyangiitis (MPA)?

What other imaging studies are indicated in the diagnosis of microscopic polyangiitis (MPA)?

What is the role of CT scanning in the evaluation of microscopic polyangiitis (MPA)?

What is the role of biopsy in the diagnosis of microscopic polyangiitis (MPA)?

Which histologic findings are characteristic of microscopic polyangiitis (MPA)?

Treatment

How is microscopic polyangiitis (MPA) treated?

How is remission induced in the treatment of microscopic polyangiitis (MPA)?

How is remission maintained in the treatment of microscopic polyangiitis (MPA)?

Which medications are used in the treatment of microscopic polyangiitis (MPA)?

Which specialist consultations are beneficial to patients with microscopic polyangiitis (MPA)?

Medications

What is the role of immunosuppressive agents in the treatment of microscopic polyangiitis (MPA)?

Which medications in the drug class Immunosuppressive agents are used in the treatment of Microscopic Polyangiitis?

Which medications in the drug class Corticosteroids are used in the treatment of Microscopic Polyangiitis?

Follow-up

What is included in the long-term monitoring of patients with microscopic polyangiitis (MPA)?

What are the possible complications of microscopic polyangiitis (MPA)?

What is included in patient education about microscopic polyangiitis (MPA)?