In 1923, Friedrich Wohlwill described two patients with a “microscopic form of periarteritis nodosa,” which was distinct from the classical form. This disease, now known as microscopic polyangiitis (MPA), is a primary systemic vasculitis characterized by inflammation of the small-caliber blood vessels and the presence of circulating antineutrophil cytoplasmic antibodies. Typically, microscopic polyangiitis presents with glomerulonephritis and pulmonary capillaritis, although involvement of the skin, nerves, and gastrointestinal tract is not uncommon. Treatment of MPA generally requires use of a cytotoxic agent (such as cyclophosphamide) in addition to high-dose glucocorticoids. Recent research has focused on identifying alternate treatment strategies that minimize or eliminate exposure to cytotoxic agents. This article reviews the history, pathogenesis, clinical manifestations, and treatment of MPA.
Microscopic polyangiitis (MPA) is an idiopathic autoimmune disease characterized by a systemic vasculitis that predominantly affects small-caliber blood vessels and is associated with the presence of antineutrophil cytoplasmic autoantibodies (ANCA). Because of its relationship to ANCA, it is often claxssified as a form of ANCA-associated vasculitis, an important subset of the primary systemic vasculitides that includes Wegener’s granulomatosis (WG), the Churg-Strauss syndrome (CSS), and renal-limited vasculitis. Because it can lead to both pulmonary capillaritis and glomerulonephritis, MPA is also a prime cause of the pulmonary–renal syndrome, a group of disorders that includes Goodpasture’s syndrome (which is associated with antiglomerular basement membrane [GBM] antibodies), systemic lupus erythematosus, and WG. This article discusses the history, pathogenesis, clinical manifestations, and treatment of MPA.
Historical overview and epidemiology
Although syphilitic aneurysms had been recognized since the 1500s, the first complete description of a primary systemic vasculitis came in 1866, when Kussmaul and Maier described the plight of Carl Seufarth, a 27-year-old journeyman tailor who had rapidly become incapacitated by fevers, myalgias, renal insufficiency, neuropathy, and abdominal pain. At autopsy, they described “[p]eculiar mostly nodular thickening . . . of countless arteries of and below the caliber of the liver artery and the major branches of the coronary arteries of the heart, principally in the bowel, stomach, kidneys, spleen, heart, and voluntary muscles, and to a lesser extent also in the liver, subcutaneous cell tissue and the bronchial and phrenic arteries.” Although the significance of these findings, which they dubbed periarteritis nodosa , was not immediately clear, this is now widely recognized as the archetypal description of polyarteritis nodosa.
For years after this description, all patients with a noninfectious arteritis were classified as having polyarteritis nodosa. In 1923, Friedrich Wohlwill described two patients who seemed to have a novel form of this disease, characterized by the presence of glomerulonephritis and nongranulomatous inflammation of the small-caliber blood vessels. This “microscopic form of periarteritis nodosa” was gradually recognized as a new entity, distinct from classic polyarteritis nodosa. In 1953, Pearl Zeek noted that this disease was pathologically similar to hypersensitivity vasculitis, preferentially involving the arterioles and venules of the visceral organs (including the lung) but often sparing the medium-caliber blood vessels. In 1950, Wainwright and Davson used the phrase microscopic polyarteritis to describe this phenotype.
In 1985, Caroline Savage and colleagues defined microscopic polyarteritis as a small-vessel vasculitis associated with focal segmental glomerulonephritis and hemoptysis. In 1994, the Chapel Hill Consensus Conference proposed the term microscopic polyangiitis to describe patients with a small-vessel vasculitis characterized by the absence of immune complex deposition on immunofluorescence, and the presence of pulmonary capillaritis and glomerulonephritis. The new name emphasized the differences between this phenomenon and classic polyarteritis nodosa, which was defined as a medium-vessel vasculitis that spared the arterioles and venules.
Despite this clear distinction, distinguishing these two phenomena clinically is not always straightforward; the classic description of polyarteritis nodosa by Kussmaul and Maier, for example, includes evidence of a small-vessel vasculitis. Moreover, the Chapel Hill Consensus Conference criteria do not always clearly distinguish MPA from other forms of vasculitis, such as WG. Regardless, the introduction of this nomenclature resulted in a rapid reduction in the prevalence of polyarteritis nodosa, because many of these patients were reclassified as having MPA.
In 1954, Godman and Churg noted that the “microscopic form of periarteritis” was closely related to WG and CSS. In the ensuing years, it gradually became clear that these three forms of systemic vasculitis were also linked by the presence of anticytoplasmic antibodies directed against neutrophils. ANCA were first reported in association with focal segmental glomerulonephritis in the 1980s. Subsequent work showed that these antibodies were associated with distinct staining patterns when alcohol-fixed neutrophils were used as a substrate. In 1988, Jennette and Falk reported that serum from patients with WG, renal-limited vasculitis, and MPA was associated with antibodies that created a perinuclear staining pattern (p-ANCA). This p-ANCA pattern is caused by antibodies against myeloperoxidase (MPO). Some authors have suggested that MPO-ANCA be used to distinguish MPA from polyarteritis nodosa, although these antibodies are also found in other forms of vasculitis, including drug-induced ANCA-associated vasculitis, CSS, and WG.
Regardless, ANCA has become a useful tool for the diagnosis of vasculitis, and may be partially responsible for the perceived increase in prevalence of the primary systemic vasculitides. Southern Sweden has the highest reported prevalence of MPA, with 94 cases per million. Overall, however, the incidence of MPA is higher in southern Europe than in northern Europe; for example, the incidence of MPA in Norway is 2.7 per million, but 11.6 per million in Spain ( Table 1 ). The incidence and prevalence of MPA in other parts of the world is less clear, but the prevalence seems to be higher in European populations.