The interval between the onset of first disease symptoms and diagnosis in MPA is substantially shorter than for patients with GPA (Wegener). This is because of the tendency for GPA (Wegener) to smolder in the upper respiratory tract and cause apparently mundane symptoms for months before leading to medical attention. In contrast, the clinical presentation of MPA is usually more obvious at the time the patient becomes aware of symptoms: cutaneous vasculitis, vasculitis neuropathy, or alveolar hemorrhage. Nevertheless, subtle and subacute presentations of MPA are known to occur, and the range of organ system manifestations is extensive.
Although MPA is classified appropriately as a “pulmonary-renal syndrome,” regarding this disorder exclusively as a disease that affects the kidneys and lungs is a major potential clinical error. The five most common clinical manifestations of MPA are glomerulonephritis (nearly 80% of patients), weight loss (>70%), mononeuritis multiplex (60%), fevers (55%), and cutaneous vasculitis (>60%). Alveolar hemorrhage, in contrast, occurs in only about 12% of patients. The major clinical manifestations of MPA are shown in Table 33–2.
Table 33–2. Major Clinical Manifestations of Microscopic Polyangiitis. ||Download (.pdf)
Table 33–2. Major Clinical Manifestations of Microscopic Polyangiitis.
|Constitutional||Weight loss, anorexia, fevers|
|HEENT||Rhinitis, tongue or other oral ulcers; occasional purpuric lesions on palate; ocular inflammation (eg, sclerouveitis) reported but rare|
|Lungs||Alveolar hemorrhage; nonspecific infiltrates; pulmonary fibrosis; pleural effusions|
|Gastrointestinal||Mesenteric vasculitis with microaneurysms in some patients|
|Kidneys||Glomerulonephritis (small-vessel vasculitis of the kidney); medium-vessel vasculitis occasionally evident on renal biopsy or demonstrated by cross-sectional imaging studies (renal infarcts)|
|Skin||Palpable purpura, ulcers, vesiculobullous lesions, splinter hemorrhages|
|Joints||Migratory pauciarthritis or polyarthritis or arthralgias; arthritis is nondestructive|
|Peripheral nerve||Sensory or motor mononeuritis multiplex|
|Central nervous system||True central nervous system vasculitis rare but reported|
Head, Eyes, Ears, Nose, and Throat
Some vasculitis experts regard the presence of any upper respiratory tract involvement as evidence that the diagnosis is GPA (Wegener), not MPA. Thus, HEENT involvement in MPA is limited generally to rhinitis or mild cases of nondestructive sinusitis. Serous otitis media may occur in MPA but unlike in GPA (Wegener), granulomatous inflammation is absent. Ocular lesions in MPA (eg, episcleritis, conjunctivitis, keratitis, and occasionally scleritis) have been reported but are less common and less severe than in GPA (Wegener).
The principal pulmonary manifestation of MPA is capillaritis, which leads to alveolar hemorrhage and often to hemoptysis. Hemoptysis may be only a late indication of bleeding. The typical radiologic features of alveolar hemorrhage are shown in Figure 33–1. Alveolar hemorrhage is associated with a worse prognosis. Interstitial fibrosis and pleuritis occur in some patients with MPA. Pulmonary fibrosis that resembles usual interstitial pneumonitis in clinical presentation is increasingly recognized as a disease manifestation of MPA. Many cases of pulmonary fibrosis are associated with previous alveolar hemorrhage, but the precise relationship between alveolar hemorrhage and fibrosis is not clear.
Radiologic features of alveolar hemorrhage. A: Chest radiograph. B: Computed tomography scan of the chest.
Renal involvement is seen in at least 80% of patients with MPA. The classic presentation of renal disease in MPA is a rapidly progressive glomerulonephritis reminiscent of GPA (Wegener) (Figure 33–2A). Some patients, however, have renal deterioration that progresses more slowly, over many months. Renal involvement may also present with urinary abnormalities such as proteinuria, microscopic hematuria, and red cell casts. Up to 40% of patients have 24-hour urinary protein excretion of more than 3 g. Proteinuria of this severity is regarded as a poor prognostic factor for renal outcome. The pathologic features of renal disease in MPA are indistinguishable from other forms of pauci-immune glomerulonephritis—namely, a necrotizing, crescentic lesion (Figure 33–2B). Compared with biopsies from patients with ANCA directed against proteinase 3, those with MPO-ANCA have a more chronic pattern of renal injury, with more glomerulosclerosis, tubular atrophy, and interstitial fibrosis.
Renal manifestations of microscopic polyangiitis. A: Red blood cell cast in a patient with glomerulonephritis secondary to microscopic polyangiitis. (Reproduced, with permission, from Stone JH, et al. Vasculitis. A collection of pearls and myths. Rheum Dis Clin North Am. 2001;27:677.) B: Glomerular crescent in a patient with microscopic polyangiitis.
Vasculitic neuropathy is a potentially devastating complication of MPA. The nerve involvement typically occurs in the pattern of a distal, asymmetric, axonal polyneuropathy (mononeuritis multiplex). The first symptoms of vasculitic neuropathy are usually sensory, with numbness, tingling, and dysesthesias. Muscle weakness and wasting follow the infarction of motor nerves (Figure 33–3). Because the named peripheral nerves are usually mixed nerves, bearing both sensory and motor fibers, patients with vasculitic neuropathy typically have both sensory and motor symptoms. Recovery from vasculitic neuropathy may take months; some patients have residual nerve damage after the disease is controlled. Although peripheral nerve lesions tend to dominate the neurologic features of MPA, central nervous system involvement by vasculitis is also described in this disease.
Muscle wasting caused by vasculitic neuropathy (mononeuritis multiplex) associated with microscopic polyangiitis.
Small-fiber neuropathy has also been reported in MPA. In patients with small-fiber neuropathy, the predominant symptoms are pain and numbness rather than motor weakness. Electrodiagnostic studies in small-fiber neuropathy patients are normal because the involved fibers are below the resolution of nerve conduction velocity assessments. Diagnosis is made by biopsy of the skin and staining for the density of small nerve fibers.
The skin manifestations of MPA include all of the cutaneous lesions associated with small-vessel vasculitis (palpable purpura, papules, vesiculobullous lesions, splinter hemorrhages). In the presence of medium-vessel involvement, nodules, ulcers, livedo reticularis (Plate 47), and digital gangrene may occur. As with most forms of cutaneous vasculitis, the lesions favor the lower extremities.
Nonspecific arthralgias and frank arthritis usually present early in the course of MPA and respond quickly to therapy. Musculoskeletal symptoms may also herald disease flares. The arthritis of MPA is migratory in nature and can assume a variety of joint patterns, from a pauci-articular syndrome of large joints to a polyarthritis of small joints. Destructive joint lesions do not occur in MPA.
The results of routine laboratory tests and specialized assays in MPA are shown in Table 33–3. All of these tests are appropriate at the initial evaluation in patients who demonstrate features consistent with MPA. The exclusion of renal disease through the careful performance of a urinalysis is essential in the evaluation and follow-up of all patients with MPA. The erythrocyte sedimentation rate and serum C-reactive protein level are useful in the longitudinal evaluation of disease activity.
Table 33–3. The Laboratory Evaluation in MPA. ||Download (.pdf)
Table 33–3. The Laboratory Evaluation in MPA.
|Complete blood cell count|
- Normochromic, normocytic anemia; acute, severe anemias possible in alveolar hemorrhage
- Mild to moderate leukocytosis common, usually not exceeding 18 × 109/L
- Moderate to pronounced thrombocytosis typical, ranging from platelet counts of 400 × 109/L to occasionally >1000 × 109/L
|Electrolytes||Hyperkalemia in the setting of advanced renal dysfunction|
|Liver function tests|
- Hepatic involvement unusual in MPA
- When present, there can be elevations of transaminases (AST/ALT) in excess of 1000 mg/dL
|Urinalysis with microscopy|
- Hematuria (ranging from mild to so high that red blood cells are too numerous to count)
- Red blood cell casts
- Proteinuria (nephritic range proteinuria in a small minority)
|Erythrocyte sedimentation rate/C-reactive protein|
- Dramatic elevations of acute phase reactants are typical, generally with good correlation to disease activity
|Rheumatoid factor||Positive in 40–50% of patients, often leading to diagnostic confusion with rheumatoid arthritis|
|C3, C4||Usually normal (or increased, because complement proteins are acute phase reactants)|
|ANCA||Positive in 70% of patients with MPA (and probably a higher percentage of patients with generalized disease)|
|Anti-GBM||A small number of patients have both ANCA and anti-GBM antibodies|
Positive ANCA assays are often instrumental in suggesting the diagnosis, but the titers of these antibodies correlate poorly in time with disease flares. Moreover, approximately 30% of patients with MPA diagnosed on a clinical basis are ANCA negative (see serologic testing, below). Thin-cut computed tomography scans are sensitive in the detection of lung disease in MPA.
By definition, MPA involves small blood vessels: arterioles, venules, and capillaries. Glomerulonephritis is the renal equivalent of small-vessel vasculitis, akin to palpable purpura in the skin and capillaritis in the lung. Renal biopsy findings, although not specific for MPA, are sufficiently characteristic to establish the diagnosis in appropriate clinical settings. Immunofluorescence studies of renal biopsies in MPA confirm the “pauci-immune” nature of the renal involvement. MPA may also involve medium-sized arteries and veins, but the identification of medium-vessel involvement is not essential to the diagnosis.
MPA is high on the differential diagnosis of leukocytoclastic vasculitis within the small blood vessels of skin lesions. The presence of extracutaneous findings and ANCA increases the likelihood of MPA. If sufficiently deep, skin biopsies may also demonstrate the involvement of medium-sized vessels in the deep dermis subcutaneous tissue layer. The finding of medium-vessel involvement eliminates certain forms of cutaneous vasculitis limited to small-vessel disease, eg, hypersensitivity vasculitis (cutaneous leukocytoclastic angiitis) and Henoch-Schönlein purpura. Direct immunofluorescence of skin biopsy tissue is also important in the exclusion of immune complex-mediated processes such as cryoglobulinemia. The involvement of both veins and arteries distinguishes MPA from classic polyarteritis nodosa, which is confined to arterial lesions.
Nerve conduction studies are an important part of the evaluation for patients with neuropathic symptoms. Nerve conduction studies may reveal the characteristic asymmetric, axonal sensorimotor neuropathy. Nerves such as the sural nerve shown to be involved in this fashion are prime candidates for biopsy, with simultaneous sampling of adjacent muscle (eg, the gastrocnemius). The sural nerve is an excellent candidate for biopsy because, in contrast to most peripheral nerves, it contains only sensory fibers. In some cases, histopathology diagnostic of vasculitis is confined to the muscle as opposed to the nerve, or vice versa. As noted, nerve conduction studies may be negative in patients with small-fiber neuropathies.
Although lung involvement can be a florid manifestation of MPA, demonstration of vasculitis on thoracoscopic or open lung biopsy is often challenging; frank capillaritis may be difficult to detect. Nevertheless, lung biopsies are often essential to exclude other processes (eg, infections or malignancies) if no other tissue options exist for biopsy.
Serologic Testing for ANCA
Three fourths of all patients with clinical diagnoses of MPA are ANCA-positive. A full discussion of ANCA is found in the chapter on GPA (Wegener) (see Chapter 32). In MPA, the classic pattern of serum reactivity upon immunofluorescence testing (with human neutrophils as the substrate) is perinuclear staining (P-ANCA). The P-ANCA pattern in MPA patients is usually caused by antibodies to MPO, a constituent of the primary granules of neutrophils. A variety of nonvasculitic conditions (Table 33–4) can also cause P-ANCA immunofluorescence, but these results are usually caused by antibodies to antigens not associated with vasculitis (eg, lactoferrin).
Table 33–4. Differential Diagnosis of Microscopic Polyangiitis. ||Download (.pdf)
Table 33–4. Differential Diagnosis of Microscopic Polyangiitis.
- Other vasculitides
- Polyarteritis nodosa
- Granulomatosis with polyangiitis (formerly Wegener granulomatosis)
- Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
- Henoch-Schönlein purpura
- Hypersensitivity vasculitis
- Mixed cryoglobulinemia
- Goodpasture disease
- Giant cell arteritis
- Drug-induced ANCA-associated vasculitis
- Pulmonary conditions
- Interstitial pulmonary fibrosis
- Idiopathic pulmonary hemosiderosis
- Systemic autoimmune conditions
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Miscellaneous nonvasculitic conditions associated with P-ANCA
- Inflammatory bowel disease
- Autoimmune hepatitis
- Sclerosing cholangitis
The combination of both a P-ANCA pattern on immunofluorescence testing and MPO-ANCA demonstrated by enzyme immunoassay has a high positive predictive value for ANCA-associated vasculitis, most commonly MPA. The other type of ANCA found in MPA is PR3-ANCA, directed against proteinase 3. This type of ANCA is usually associated with a cytoplasmic (C-ANCA) pattern of immunofluorescent staining. Despite advances in ANCA testing techniques, histopathology remains the cornerstone of diagnosis in MPA. When the diagnosis is unconfirmed, all reasonable attempts to obtain a tissue diagnosis should be pursued.