Microscopic Polyangiitis

Etiology

The etiopathogenesis of MPA and related vasculitides has largely been attributed to ANCAs, which are host-derived autoantibodies targeting normally shielded neutrophilic antigens. These antibodies react against primary granules in neutrophils and monocytes. The formation of these antibodies has been hypothesized to be a 2-step process.[4] In the first step, neutrophils are exposed to inflammatory cytokines, leading to the surface expression of antigens such as myeloperoxidase (MPO). Next, predisposing genetic, environmental, and other factors lead to ANCA production. In the second step, these ANCAs damage the host vasculature by triggering inflammation and cytokine production.[5]

Although anti-MPO is the primary ANCA associated with MPA, anti-proteinase 3 (PR3) can also be present in some cases. Estimates suggest that approximately 70% of patients with MPA are anti-MPO–positive, 20% are anti-PR3–positive, and 10% are ANCA-negative.[6] Less specific ANCA antigens include cathepsin G, lactoferrin, elastase, defensin, α-enolase, moesin, leukocidin, and bactericidal permeability increasing protein, although their pathogenicity is considered to be low.[6]

Lysosomal-associated membrane protein 2 (LAMP-2) antibodies are of particular interest in ANCA-associated vasculitis because they are present in patients with both anti-MPO and anti-PR3 antibodies and may contribute to the disease pathology. Moreover, LAMP-2 antibodies have been detected in patients with active ANCA-associated vasculitis who are negative for MPO and PR3 antibodies. Some evidence suggests that LAMP-2 antibodies may correlate better with disease activity than anti-MPO or anti-PR3 antibodies.[7][8]

About 90% of patients with active MPA test positive for ANCA; however, not all cases of ANCA positivity correlate with active disease. This suggests that other factors may also contribute to the disease's etiopathogenesis. These factors include (but are not limited to):

• Infectious causes: The considerable overlap between the clinical presentations of various infectious processes and MPA leads to this implication. Chronic nasal carriage of Staphylococcus aureus has been proposed as a potential contributing factor.

• Genetic factors: Recent genome-wide studies conducted in Europe have identified genes such as HLA-DP, HLA-DR3, and alpha-1 antitrypsin as potentially involved in the pathogenesis of ANCA-associated vasculitis.[9][10]

• Environmental factors: UV light, air pollution, and silica exposure have also been suggested as possible triggers for ANCA-associated vasculitis.[8]

• Drugs: Certain medications, including hydralazine, thionamides, sulfasalazine, and minocycline, have been observed to be associated with the incidence of ANCA-associated vasculitis.[10][11] This form of vasculitis is often anti-MPO positive and is covered more extensively in the StatPearls' companion resource, "ANCA-Associated Vasculitis."

Epidemiology

Due to the recent differentiation of MPA from other ANCA-associated vasculitides, comprehensive demographic data for its prevalence in the US population are not widely available. A study conducted in Rochester, Minnesota, over a 20-year period estimated the annual incidence of ANCA-associated vasculitis at 3.3 per 100,000, with a prevalence of 42.1 per 100,000. The incidence of GPA and MPA was approximately 1.5 per 100,000.[12] An increase in the prevalence of MPA over the past 2 decades is likely due to improved recognition and the availability of ANCA testing. The global incidence of MPA is estimated to be 20 per million.[6] 

Evidence suggests that MPA is more common in China and Japan, whereas GPA is more prevalent among populations of European descent.[6] The median age of onset for MPA is between 50 and 60. The disease appears to have about equal prevalence between males and females.[8]

Pathophysiology

While anti-MPO is the primary ANCA associated with MPA, anti-PR3 is also present in some cases. Notably, it is estimated that in MPA, approximately 70% of patients are anti-MPO–positive, 20% are anti-PR3–positive, and 10% are ANCA-negative.[6] 

The clinical manifestations of MPA result from the activation of primed neutrophils and MPO-ANCA, which interact with receptors on the endothelial surface.[13] This process leads to a range of symptoms affecting the renal, pulmonary, and other capillary beds. Patients may present with an insidious onset of systemic signs such as fever, malaise, or weight loss; however, the onset is more commonly acute, with complaints of arthralgia and flu-like symptoms. MPA is a small vessel vasculitis characterized by pauci-immune, necrotizing inflammation without clinical or pathological evidence of granulomatous involvement, often leading to necrosis and bleeding.[6] 

Renal manifestations are extremely common in MPA, with 80% to 90% of individuals experiencing some form of glomerulonephritis at onset or as the disease progresses. The most common renal manifestation is a "pauci-immune" form of rapidly progressive glomerulonephritis. Clinical presentations can range from asymptomatic hematuria, sub-nephrotic proteinuria, and elevated serum creatinine to overt renal failure. Pulmonary manifestations often include alveolar hemorrhage, which may sometimes be the first presenting symptom of the disease.[14]

Histopathology

Histopathological evidence of vasculitis is the gold standard for confirming the diagnosis of MPA and other ANCA-associated vasculitides. The most commonly sampled tissues are from the kidneys, skin, and lungs. Diffuse capillaritis is a typical pulmonary finding in patients with MPA, distinguishing it from GPA, which is characterized by the presence of granulomatous lesions. Skin biopsy yields acute or chronic leukocytoclastic vasculitis with neutrophilic infiltrate in the narrow caliber vessels of the superficial dermis. Renal biopsy findings in MPA typically range from mild focal or segmental to diffuse necrotizing and sclerosing glomerulonephritis, often presenting as crescentic glomerulonephritis. These biopsies usually show minimal to no immune complex deposits on light and immunofluorescent microscopy, a characteristic described as "pauci-immune" (see Image. Histopathological Changes in Microscopic Polyangiitis Showing Fibrosis).[15] 

The importance of renal biopsy is underscored by the fact that the severity of renal involvement observed on histopathological evaluation correlates closely with clinical disease activity.[16] This makes biopsy a crucial tool for guiding the management of the condition and decisions regarding tapering immunosuppressive therapy. In some cases, the presence of immune complex deposits in the glomeruli may be associated with more severe systemic signs and symptoms. Please see StatPearls' companion resource, "Rapidly Progressive Glomerulonephritis," for more information.

History and Physical

Patients with MPA may present with constitutional symptoms, including insidious onset fever, arthralgia, myalgia, and weight loss. Other manifestations include urinary abnormalities, cough with or without hemoptysis, skin examination findings consistent with palpable purpura, mononeuritis multiplex, seizures, other nonspecific neurological complaints, abdominal pain, gastrointestinal bleeding, sinusitis, and chest, testicular, and ocular pain. Some patients may present with acute onset of fulminant disease with frank hemoptysis, hematuria, or even renal failure.

Renal Manifestations

The primary renal feature of MPA is rapidly progressive glomerulonephritis.[17] Previous studies reported that 80% to 90% of patients with MPA experience renal manifestations, which can range from asymptomatic urinary sediment to end-stage renal failure requiring renal replacement therapy. Common clinical features of renal involvement due to glomerulonephritis include microscopic hematuria, proteinuria, and the presence of granular or red blood cell (RBC) casts in the urine.[18]

Pulmonary Manifestations

Pulmonary involvement is thought to be observed in 25% to 55% of cases. However, pulmonary symptoms may be more common than previously thought. A single-center study found that 80% of MPA patients were observed to have symptoms of pulmonary involvement, and 92% were found to have radiographic changes.[19] Although the most common pulmonary feature is diffuse alveolar hemorrhage, some patients may develop chronic interstitial fibrosis, causing respiratory failure.[20] Common manifestations of alveolar hemorrhage include hemoptysis, cough, dyspnea, and pleuritic chest pain.[21] Unlike GPA and EGPA, upper respiratory tract signs are rare.

Skin Manifestations

Skin lesions are observed in 30% to 60% of patients with MPA, and these lesions are the initial presenting feature in 15% to 30% of cases.[22][23] These skin manifestations include palpable purpura, livedo reticularis, urticaria, nodules, and ulcers with necrosis. Additionally, skin manifestations have been associated with joint pain in patients with MPA (see Image. Typical Skin Manifestations Observed in Microscopic Polyangiitis).[24]

Gastrointestinal Manifestations

Abdominal pain is the most common gastrointestinal symptom in MPA. Although gastrointestinal bleeding can occur, massive hemorrhage is rare.[25]

Neurological Manifestations

Neurological involvement is common in MPA, with peripheral neuropathy occurring more frequently than central nervous system (CNS) involvement. Predominant peripheral nervous system features include distal symmetrical polyneuropathy and mononeuritis multiplex. Sural nerve biopsies often reveal necrotizing vasculitis in up to 80% of cases, and nerve conduction studies may show acute axonopathy.[26] Rarely, patients may present with posterior reversible encephalopathy syndrome.[27] CNS manifestations can vary and include cerebral hemorrhage, nonhemorrhagic cerebral infarctions, and pachymeningitis.[28]

Physical Examination

Findings from the physical examination of a patient with MPA may reveal systemic signs such as general malaise, fever, or weight loss. Skin examination findings may include leukocytoclastic angiitis, palpable purpura, livedo reticularis, skin ulcerations, necrosis, gangrene, necrotizing nodules, digital ischemia, and urticaria. Pulmonary examination may reveal rales or bronchial breath sounds, particularly in cases of pulmonary capillaritis. Neurological examination might demonstrate motor or sensory deficits localized to a particular dermatome. Cardiovascular findings may include hypertension, signs of heart failure, myocardial infarction, and pericarditis. Findings from the gastrointestinal examination include bleeding, bowel ischemia, and perforation. The ocular examination may reveal retinal hemorrhage, scleritis, and uveitis. Other physical findings will vary depending on the involved vascular bed.

Evaluation

Evaluating a patient with suspected MPA requires a comprehensive clinical, radiological, histopathological, and laboratory assessment. The initial step is a detailed clinical evaluation to determine the site and extent of involvement across various organ systems.

Laboratory Studies

As noted above, although anti-MPO is the primary ANCA associated with MPA, anti-PR3 can also be present in some cases. ANCA levels are most closely correlated with renal activity compared to other organ systems.[8] Other useful laboratory evaluations include:

• The complete blood cell count (CBC) shows leukocytosis and anemia.
• The erythrocyte sedimentation rate (ESR) is usually elevated.
• Blood urea nitrogen (BUN) and serum creatinine levels are elevated in cases of renal failure.
• Urine examination shows abnormal urine sediment, proteinuria, hematuria, leukocyturia, and RBC casts.
• Blood cultures may be performed to rule out bacterial endocarditis.
• C3 and C4 levels are usually normal on complement testing.

Imaging Studies

A chest radiography and computed tomography (CT) scan of the chest should be obtained to assess for pulmonary lesions in patients presenting with hemoptysis or pulmonary fibrosis.[29] These imaging studies help differentiate between GPA and MPA, as GPA often shows cavitary and nodular lesions on radiological evaluation. A CT scan of the abdomen may also be performed to evaluate for pancreatitis or mesenteric angiography to distinguish MPA from polyarteritis nodosa.[30]

Other Studies

• Electrocardiography (ECG) is used to evaluate for myocardial infarction, pericarditis, or heart failure.
• Gastrointestinal endoscopy is performed in cases of gastrointestinal bleeding.
• Electromyography (EMG) and nerve conduction studies are utilized in cases of clinical evidence of neuropathy.[31]

Histopathological Evaluation 

A histopathological specimen (skin, renal, or lung biopsy) should be obtained whenever possible to identify evidence of vasculitis and immune deposits. The extent of inflammation observed on renal biopsy can be used to assess disease activity and guide treatment decisions.

Treatment / Management

Currently, the American College of Rheumatology and the European Alliance of Associations for Rheumatology (ACR/EULAR) are developing criteria for the treatment of ANCA-associated vasculitis. Based on new clinical trial data, recent recommendations suggest classifying disease manifestations into organ/life-threatening or non-organ/life-threatening categories rather than "severe" or "not severe." Examples of organ/life-threatening manifestations include glomerulonephritis, pulmonary hemorrhage, cardiac involvement, and retroorbital disease. Non-organ/life-threatening manifestations include skin involvement, myositis, and non-cavitating pulmonary nodules.[32]

The treatment of MPA involves using immunosuppressive agents in various combinations, divided into two phases: induction and maintenance. Commonly used agents include cyclophosphamide, glucocorticoids, rituximab, azathioprine, methotrexate, and, when indicated, plasmapheresis. 

The 2022 EULAR recommendations for the management of ANCA-associated vasculitis apply to both GPA and MPA.[32] Treating EGPA follows a different set of guidelines. A key distinction between GPA and MPA is that patients with the clinical syndrome of GPA and PR3-ANCA positivity have a higher relapse risk compared to those with MPA or anti-MPO positivity. Additionally, persistent ANCA positivity, despite clinical remission, is associated with an increased risk of relapse.[32] Although extending immunosuppressive therapy beyond 24 months may reduce relapse risk, the heightened risk of infection may not warrant this prolonged treatment course.

The 2022 EULAR recommendations include:

• For new-onset organ/life-threatening MPA and GPA, remission should be induced with glucocorticoids combined with either rituximab or cyclophosphamide. Rituximab is preferred in cases of relapsing disease. No significant differences are observed in outcomes between using 2-dose or 4-dose infusions of rituximab.[33]
(A1)

• For new-onset non-organ/life-threatening MPA, remission should be induced with glucocorticoids and rituximab. In some cases, methotrexate or mycophenolate mofetil can be substituted for rituximab. Cyclophosphamide is generally not preferred due to a higher incidence of adverse effects despite its reduced efficacy. Additionally, a lower prednisolone dose of 0.5 mg/kg/d may also be considered.

• The induction regimen should include oral glucocorticoids at a weight-dependent dose of 50 to 75 mg daily, with prednisolone tapered to 5 mg daily over 4 to 5 months.

• Avacopan is an oral C5a-receptor antagonist that helps block neutrophil attraction and activation. The ADVOCATE trial demonstrated that avacopan can induce remission when used alongside rituximab or cyclophosphamide, reducing the need for glucocorticoid exposure. Avacopan was approved by the US Food and Drug Administration (FDA) in 2021 to treat severe ANCA-associated vasculitis.[34]

• Plasma exchange can induce remission in patients with glomerulonephritis and a serum creatinine level greater than 3.39 mg/dL (300 μmol/L). Routine use of plasmapheresis for alveolar hemorrhage in MPA and GPA is not recommended. However, it is often used as "salvage" therapy, particularly for patients with a serum creatinine level exceeding 5.7 mg/dL.[35] A meta-analysis suggests that plasmapheresis reduces the risk of end-stage renal disease but is associated with an increased risk of infections within the first year.[36]
(A1)

• Rituximab is recommended for maintaining remission. Azathioprine or methotrexate may also be considered; however, their use should be reserved for patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73m².[35] 

• For new-onset disease, maintenance therapy should continue for 24 to 48 months after remission begins. A longer treatment duration should be considered for patients with relapsing disease.

• Treatment decisions should be guided by clinical assessment rather than ANCA levels or CD19+ B lymphocyte counts.

• If rituximab is administered, serum immunoglobulin levels should be measured before each dose. 

• For patients receiving rituximab, cyclophosphamide, or high-dose glucocorticoids, prophylaxis with trimethoprim-sulfamethoxazole should be provided.

Differential Diagnosis

Many conditions may mimic ANCA-associated vasculitis/MPA and must be excluded before establishing a diagnosis. Some of these processes include:

Infectious Etiologies

• Infective endocarditis
• Rocky Mountain spotted fever and other tick-borne vasculitides
• Disseminated fungal infections

Malignancies

• Atrial myxomas
• Lymphomas
• Carcinomatosis

Drug Toxicities

• Cocaine
• Amphetamines
• Ergot alkaloids
• Levamisole

Other Autoimmune Conditions

• Amyloidosis
• Goodpasture disease [37]
• Sarcoidosis
• Polyarteritis nodosa
• Leukocytoclastic vasculitis
• Granulomatosis with polyangiitis
• Eosinophilic granulomatosis with polyangiitis
• Cryoglobulinemia

Toxicity and Adverse Effect Management

The immunosuppressive agents used in managing ANCA-associated vasculitis have severe adverse effects, which may be even more debilitating than the manifestations of the disease. 

Glucocorticoids

• Osteoporosis [38]
• Cataract
• Glaucoma
• Diabetes mellitus
• Electrolyte abnormalities
• Avascular necrosis of bone

Cyclophosphamide

• Bone marrow suppression
• Hemorrhagic cystitis [39]
• Bladder carcinoma
• Myelodysplasia

Methotrexate

• Hepatotoxicity
• Pneumonitis
• Bone marrow suppression

Azathioprine

• Hepatotoxicity
• Bone marrow suppression

Rituximab

• Progressive multifocal leukoencephalopathy
• Opportunistic infections

Prognosis

The 5-year estimated survival rate for patients with MPA ranges from 45% to 76%, which is significantly worse than that for GPA or EGPA, largely due to renal disease.[6][40]

Long-term morbidity in a cohort of 296 patients with MPA or GPA was associated with the severity of the primary disease, the number of relapses, older age, and the duration of glucocorticoid treatment. In a 7-year follow-up post-diagnosis, the mean duration of glucocorticoid therapy was 40.4 months.[41] 

Complications

If left untreated, MPA can lead to permanent organ damage, with kidney failure being the most common complication. Other complications depend on the specific organ systems involved. Research has shown that older age, diastolic hypertension, and positive PR3-ANCA status correlate with an increased risk of cardiovascular events.[42]

The medications used to treat MPA can also lead to significant adverse effects. For instance, cyclophosphamide is strongly associated with an increased risk of bladder cancer. Additionally, steroids are known to cause bone loss, hyperglycemia, muscle weakness, and skin issues.