Microscopic Polyangiitis

Microscopic polyangiitis is a small vessel necrotizing vasculitis, a part of a large spectrum of disorders termed as anti-neutrophil-cytoplasmic-antibody (ANCA)-associated vasculitides (AAV). This umbrella term includes granulomatosis with polyangiitis, microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA or Churg-Strauss disease), and renal limited vasculitis (RLV). This classification of vasculitides based on the type of vessels involved and the underlying etiology was first laid down by the International Chapel Hill Convention Conference on the Nomenclature of Vasculitides (CHCC 2012).[1]

The term microscopic polyarteritis was introduced in the literature by Davson in 1948 to describe the pattern of glomerulonephritis seen in patients of polyarteritis nodosa.[2] It was later described as a pattern of necrotizing vasculitis, without immune complex deposition, affecting small vessels such as the capillaries, venules, and arterioles. The disease commonly involves glomerulonephritis, pulmonary capillaritis, and other systemic capillary beds. It shows considerable overlap with granulomatosis with polyangiitis. The absence of granulomatous inflammation involving the upper respiratory tract and the presence of pulmonary capillaritis is said to differentiate MPA from GPA. MPA is also included in a group of disorders termed pulmonary-renal syndrome, which includes MPA, GPA, Goodpasture disease, and systemic lupus erythematosus (SLE).[3]

The etiopathogenesis of MPA and other related vasculitides has largely been attributed to anti-neutrophil-cytoplasmic antibodies or ANCA. These are host-derived auto-antibodies against shielded neutrophilic antigens. These antibodies react against primary granules present in neutrophils and monocytes. The formation of these antibodies has been hypothesized to be a 2-step process.[4] The first step involves exposure of neutrophils to inflammatory cytokines leading to surface exposure of cryptogenic antigens like myeloperoxidase or MPO. Next, predisposing genetic, environmental, and other factors result in the production of MPO-ANCA. In the second step, these MPO-ANCA cause damage to the host vasculature by reacting and crosslinking neutrophils to the endothelial receptors.[5]

Only 70% of cases of MPA have ANCA at the time of diagnosis, and most of the cases of limited MPA do not have ANCA at all. This has lead to the understanding that other factors may also be playing a role in its etiopathogenesis. These include, but are not limited to:

• Infectious causes: There is considerable overlap in the clinical presentation of various infectious processes and MPAN leading to this implication. A possible role of chronic nasal carriage of Staphylococcus aureus has been suggested in relapsing GPA as well.[6]
• Drugs: Various drugs like hydralazine, thionamides, sulfasalazine, and minocycline, among others, have been observed to be associated with the incidence of ANCA-associated vasculitis.[7]
• Genetic factors: More recently, A genome-wide study conducted in Europe has implicated genes like HLA-DP, HLA-DR3, and alpha-1 antitrypsin in the pathogenesis of ANCA-associated vasculitides.[8]

Due to the recent differentiation of MPA from other AAV, widespread data regarding its demographic factors in the American population is not available yet. One study conducted in Rochester, Minnesota, over a period of 20 years estimated the annual incidence of AAV to be 3.3 per 100,000 with a prevalence of 42.1 per 100,000. The incidence of GPA and MPA were approximately 1.5 per 100,000.[9] Studies from European countries have revealed a comparatively higher incidence and prevalence of AAV, with the highest incidence rates seen in Spain and the United Kingdom, 11.6 and 5.8 cases per million population, respectively.[10] The disease is more prevalent among males, with a peak incidence around the age of 40.

As explained above, the clinical manifestations of MPA stem from activation of primed neutrophils and MPO-ANCA with receptors present on the endothelial surface. These lead to a variety of manifestations affecting the renal, pulmonary, and other capillary beds. Individuals may present with an insidious onset of systemic signs like fever, malaise, or weight loss, but more commonly, the onset is acute in patients complaining of arthralgia and flu-like symptoms.[11]

Renal manifestations are most common, and up to 80% to 100% of individuals have some form of glomerulonephritis at onset or with disease progression.[11] The most common manifestation is a "pauci-immune" form of rapidly progressive glomerulonephritis (RPGN). Clinical presentation may vary from asymptomatic hematuria, sub-nephrotic proteinuria, a rise in serum creatinine, or overt renal failure.[12] Pulmonary manifestations may be in the form of alveolar hemorrhage, which is sometimes the first presenting symptom of the disease. Cutaneous manifestations include leukocytoclastic-vasculitis, palpable purpura, or nodular and ulcerative lesions that commonly involve the lower extremities. Occasionally ocular manifestations (conjunctivitis, episcleritis, optic neuropathy) and neurological manifestations (mononeuritis multiplex, cranial neuropathy, among others) may also be seen.

Histopathological evidence of vasculitis is the gold standard for confirmation of the diagnosis of MPA and other AAV. The most commonly sampled tissues are renal, skin, and lung tissue. Pulmonary findings in MPA is most commonly a form of diffuse capillaritis (distinguishing it from GPA that characteristically shows granulomatous lesions). Skin biopsy yields acute or chronic leukocytoclastic vasculitis with neutrophilic infiltrate in the narrow caliber vessels of the superficial dermis. Renal biopsy most commonly varies from mild focal or segmental to a diffuse necrotizing and sclerosing glomerulonephritis that shows minimal to no immune complex deposits on light and immunofluorescent microscopy ("pauci-immune"). The importance of renal biopsy lies in the fact that the severity of renal involvement on histopathological evaluation correlates clinically with disease activity.[13] It thus plays an important role in guiding patient management and tapering immunosuppressive therapy. Although this is the mainstay, it has been shown that many patients may have diffuse interstitial nephritis without involving the glomeruli, which may pose a difficulty in diagnosis. Moreover, a few may have immune complex deposits in the glomeruli and experience more severe systemic signs and symptoms.[14]