Microscopic Polyangiitis
MPA was first recognized as a distinct entity by Davson and colleagues in 1948.[132] They described this as subgroup of polyarteritis nodosa, distinguished by the presence of segmental necrotizing glomerulonephritis.
MPA was not included in the American College of Rheumatology (ACR) classification scheme, and it is assumed that most of such patients were labeled as having polyarteritis or, less frequently, WG. The Chapel Hill International Consensus Criteria[1] defined MPA as a necrotizing vasculitis with few or no deposits affecting small vessels (i.e., capillaries, venules, or arterioles). They also noted that MPA frequently is associated with necrotizing glomerulonephritis and pulmonary capillaritis. MPA is also occasionally referred to as "microscopic polyarteritis," but MPA is preferred because it distinguishes the syndrome more clearly.
The general clinical features of MPA, collected from four large clinical series,[133][134][135][136] are summarized in Table 83-1 and reflect the propensity for widespread target-organ involvement. The disease tends to affect males more frequently than females, with male-to-female ratios ranging from 1[133] to 1.8.[134] The age of onset is generally in the fourth or fifth decade but can range from early childhood to old age.[137] The onset may be hyperacute with rapidly progressive glomerulonephritis and pulmonary hemorrhage, presenting as the pulmonary renal syndrome, or at times may be extremely insidious with several years if intermittent constitutional symptoms, purpura, mild renal disease, and even periodic bouts of hemoptysis.
Table 83-1 -- CLINICAL FEATURES OF MICROSCOPIC POLYANGIITIS (PMA)
| Clinical Feature | Percentage * |
| Constitutional symptoms | 76–79 |
| Fever | 50–72 |
| Renal disease | 100 |
| Arthralgias | 28–65 |
| Purpura | 40–44 |
| Pulmonary disease (hemorrhage, infiltrates, effusion) | 50 |
| Neurologic disease (central, peripheral) | 28 |
| Ear, nose, throat | 30 |
| Percentage of studied populations totaling 150 patients from four studies[133][134][135][136] |
The universal presence of renal disease in most large series[133][134][135][136] reflects both the common involvement of the kidney and the ascertainment bias of reporting by nephrology groups. Clearly MPA can be seen in the absence of renal disease, although it is less common. The course of the renal disease is also variable, but a rapidly progressive course has been frequently reported in series reported by nephrology groups. Dialysis has been required in between 25 and 45 percent of patients in several large series.[134][135] The renal lesion of MPA is that of necrotizing glomerulonephritis. The characteristic features of this lesion are segmental necrosis, crescent formation (extracapillary proliferation), slight or no endocapillary proliferation, slight or no immune deposits by immunohistology, and slight or no electron-dense deposits by electron microscopy.[138] This lesion is clearly distinct from immune complex-mediated glomerulonephritis and antiglomerular basement membrane antibody-mediated disease but is not distinguishable from the glomerular lesion of WG or idiopathic rapidly progressive crescentic glomerulonephritis
Lung involvement is common in MPA and is present in more than half of reported cases in most series. Diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement and has been reported in 12 to 29 percent of patients in several series.[133][134][135][136] The clinical manifestations may range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia, but the onset is acute in most patients. The radiographic features of DAH are nonspecific, demonstrating alvelolar infiltration ranging from patchy to diffuse. The characteristic finding of alveolar infiltrates in the absence of congestive heart failure or infection is helpful, but the clinical differentiation of these disorders in the acutely ill patient may at times be difficult. The absence of frank hemoptysis should never dissuade serious consideration of possible, even massive, DAH, as it may be absent in up to one third of patients.[139] An alternative presentation of lung involvement in MPA is that of interstitial fibrosis based on recurrent episodes DAH. This generally occurs after a prolonged (i.e., many years) history of such events.[139]
The characteristic histopathology of MPA is that of pulmonary capillaritis ( Fig. 83-10 ). In this lesion there is disruption of the alveolar interstitium, leading to loss of integrity of the constituent capillary network and resulting in RBC leakage into the alveolar spaces. The alveolar wall expands and becomes edematous and ultimately undergoes fibrinoid necrosis. Characteristically, there is prominent neutrophilic leukocytosis of the alveolar septum, often accompanied by leucocytoclasia. Immunohistology, similar to the kidney, rarely demonstrates immune deposits. Other findings include capillary thrombosis, type II epithelial cell hyperplasia, and lymphoplasmocytic infiltration.[139] This clinical and histologic picture can be seen in a variety of conditions commonly observed in WG, SLE, and in an isolated form.[139][140] When DAH occurs in an isolated form, it may be in the presence or absence of MPO-ANCA.[139]
Other clinical features of MPA are similar to the other major forms of ANCA-associated small vessel vasculitis, as well as classic polyarteritis nodosa. Arthralgia, myalgia, and fever are common (see Table 83-1 ). Skin involvement is common as well and most frequently manifests as palpable purpura. Peripheral neuropathy is observed in the minority of patients and appears to be less common than the other ANCA-associated syndromes. Involvement of the ears, nose, and throat is infrequent and when present should seriously raise the question of missed WG in which granulomas have either been overlooked or missed by sampling error on biopsy.
The diagnosis of MPA may at times be problematic. There is a great variability in the presenting manifestations, as well as the intensity of the illness. Clearly MPA should be considered in any patient with the general features of a systemic vasculitis, such as prolonged unexplained fever, unexplained multisystem organ involvement (especially renal and pulmonary), and palpable purpura. MPA is prominent in the differential pulmonary renal syndromes along with WG, SLE, and antiglomerular basement membrane disease.
Although the diagnosis of MPA may at times be based on clinical and laboratory findings, it is preferred to secure the diagnosis with histology. The most accessible and rewarding tissues are skin, kidney, and lung. It must be emphasized that in none of the organs is there a specific histopathologic picture of MPA. However, the presence of pulmonary capillaritis, necrotizing pauci-immune glomerulonephritis, or leukocytoclastic vasculitis in skin can secure the diagnosis in the patient with the appropriate degree of pretest probability and the necessary exclusions. As noted, MPO-ANCA is present in 60 to 85 percent of patients, but occasionally, patients may be PR3-ANCA positive. Diagnosis of MPA based solely on a positive MPO-ANCA in a patient with low test probability is fraught with risk, considering the gravity of the therapy.
Differentiating MPA from classic polyarteritis is often based on the pattern of renal disease, which differs dramatically between the two. In classic polyarteritis, the glomerulus is largely spared and extraglomerular vascular disease (i.e., vascular nephropathy) is common. Pulmonary involvement is uncommon in classic disease, and hemorrhage is virtually never encountered. Hypertension and peripheral neuropathy are much more common in classic polyarteritis as well. From the laboratory perspective, classic polyarteritis is rarely PR3- or MPO-ANCA positive, and MPA is rarely associated with hepatitis B. Angiographically, classic polyarteritis nodosa is far more frequently associated with microaneursyms, which are rare in MPA.[141]
Differentiation from WG may at times be difficult because of the random nature of the granulomas in this condition. Prominent involvement of the upper respiratory tract or the presence of PR3-ANCA should seriously raise the possibility of WG because the occurrence of these findings are unusual, though not unheard of, in MPA.
The treatment of MPA is based on the same therapeutic principles as those outlined for WG. The majority of information on therapy and prognosis of this disorder is based on retrospective analysis of case series.[134][135][142][143] Most investigators agree that in the presence of serious renal or pulmonary disease, combined therapy with high-dose GC and CTX is indicated. A recent study by the French Vasculitis Study Group,[144] representing the longest follow-up of a cohort including MPA (88.3 months), has reaffirmed that combined GC and CTX is beneficial, especially in severe disease. In this complex study representing a pooled analysis of four prospective trials of different therapeutic agents, there was an overall mortality of 30 percent throughout approximately 7 years of follow-up. Mortality, not surprisingly, was seen in those with a high incidence of renal, GI, cardiovascular, or CNS involvement. Survival rates were superior among the most severely ill patients treated with combination of GC and CTX versus those treated with GC alone. There are limited data supporting a role of apheresis in those with the most advanced renal disease, including those who are dialysis dependent.[145] Lastly there are also uncontrolled reports of successful therapy with IVIg.[146] Whatever therapy is employed, there is a significant risk of relapse in MPA, particularly when therapy is being tapered or after therapy is discontinued.[147] Careful follow-up, including serial monitoring of clinical symptoms and renal function with serial examination of the urinary sediment, is important for long-term management
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