ReviewPolyarteritis nodosa: A contemporary overview
Introduction
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly targets medium-sized arteries [1], [2]. Small arteries may also be involved, but small vessels, including arterioles, capillaries, and venules, are not [1].
The first complete macroscopic description of PAN was provided from K. Rokitansky in 1842. This pathologist described the presence of aneurysms without microscopic examination; therefore, the inflammatory nature of this disease was not recognized [3].
In 1866, A. Kussmaul and R. Maier provided a clinical description of a patient, including a post-mortem histological examination, arriving at a diagnosis of vasculitis [4]. Kussmaul and Maier introduced the term “periarteritis nodosa” to describe the nodules observed in intermediate-sized vascular arteries. These nodules resulted from aneurysm formation secondary to the involvement of all layers of the artery; therefore, the term was changed to “polyarteritis nodosa” [5], [6]. However, it was not until 1931 that Lindberg first recognized PAN limited to skin [7]. In 1970, Trepo and Thivolet reported the association of PAN with hepatitis B virus (HBV) infection [8], and it soon became obvious that a substantial part of PAN cases were associated with HBV.
Since the first description, the term “polyarteritis nodosa” has generically been used to describe any form of systemic vasculitis of unknown cause. The lack of an understanding of this disease, which has been described for nearly 150 years, reflects the fact that there is no uniform definition of PAN associated with a condition exhibiting protean and overlapping clinical manifestations, and no specific serologic diagnostic tests have been developed.
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Epidemiology
Although PAN has become an even more uncommon disease and a rare form of vasculitis, the precise frequency of this disease is difficult to determine. While a true change in PAN epidemiology cannot be excluded, there is little doubt that the current rarity of PAN largely reflects the gradual narrowing of the spectrum of systemic vasculitides.
In European countries, the incidence of PAN ranges from 0 to 1.6 cases per million, and the prevalence of this disease is approximately 31 cases per million
Etiopathogenesis
The pathogenesis of “idiopathic PAN” remains enigmatic, although the clinical responses to immunosuppressive therapy suggest that immunological mechanisms play an active pathogenic role.
As in other forms of vasculitis, the presence of impaired endothelial function could reflect direct endothelial cell activation and damage resulting from primary inflammatory vasculitis or proinflammatory cytokines or antibodies (i.e., anti-endothelial cell antibodies) [15], [16]. Activated endothelial cells
Clinical manifestations
The disease spectrum ranges from involving a single organ to polyvisceral failure. The progression from one end of the spectrum to the other is uncommon. Virtually, any organ might be affected; however, for reasons that are not understood, PAN does not affect the lungs [12], [19], [22], [23], [24].
The occlusion or rupture of inflamed arteries might produce tissue ischemia or hemorrhage in a variety of organs and systems. Consequently, PAN might generate a wide constellation of clinical
Clinical variants of PAN
In addition to the systemic idiopathic form (henceforth called “idiopathic generalized PAN”), the PAN spectrum includes 2 well-accepted clinical variants, namely, “cutaneous PAN” and “hepatitis B virus (HBV)-associated PAN.” These clinical forms are important, as these clinical variants represent specific therapeutic implications.
In 1931, cutaneous PAN was recognized [7] as a skin-restricted form of medium-sized-vessel vasculitis, exclusively involving the limbs and predominantly involving the
Histopathology
Vascular inflammatory lesions are characteristically segmental and predominate in branching points [2]. The occurrence of PAN lesions at arterial branching sites might result from hydrostatic forces or the increased expression of adhesion molecules and increased numbers of intimal macrophages at these sites [40], [41].
Inflammatory infiltrates are typically mixed and include lymphocytes, macrophages, and variable numbers of neutrophils and eosinophils [2]. Fibrinoid necrosis is frequently
Diagnosis
No test or clinical finding reliably indicates the presence or absence of PAN; therefore, the diagnosis of this disease requires the integration of clinical, angiographic, and biopsy findings.
Clinically, PAN is suspected in patients with marked constitutional symptoms and multisystem involvement [19].
The demonstration of medium-sized vessel microaneurysms is the hallmark of PAN. The typical arteriographic lesions in PAN are arterial saccular or fusiform microaneurysms (1–5 mm in diameter), which
Differential diagnosis
The differential diagnosis of this disease with other vasculitis and diseases that mimic PAN (i.e., sepsis, endocarditis, and left atrial myxoma) is critical [23].
Hypereosinophilia might occasionally be observed, but when present, eosinophilic granulomatosis with polyangiitis (Churg–Strauss) must be ruled out [56].
ANCA are typically negative, and the detection of these antibodies in the context of necrotizing vasculitis strongly suggests other systemic vasculitis commonly associated with the
Prognosis
PAN is an acute and occasionally fatal disease [61]. Relapses occur in fewer than 10% of HBV-PAN cases and up to 20% of idiopathic PAN cases [62], [63].
The overall prognosis of this disease has improved in recent decades, primarily reflecting early diagnosis, rapid initiation of more effective treatments, and improved patient/therapy monitoring [64]. The 5-year survival rate for untreated PAN is 13% [65], [66]. The outcome of PAN has improved in patients receiving treatment, and the 5-year
Treatment of idiopathic generalized PAN
Glucocorticoids and cyclophosphamide represent the cornerstone of PAN therapy. The distribution of the involved organs and disease progression are the two principal determinants for treating patients with PAN.
Current therapeutic approaches consider treating mild forms of primary PAN (with FFS = 0) with corticosteroids alone. When remission is achieved, prednisone or prednisolone is typically used at doses of 1 mg/kg/day with subsequent tapering [63], [69].
In the presence of critical organ
Conclusion
Over 150 years after the initial case report of Kussmaul and Maier, a considerable lack of knowledge about classical PAN remains. Kussmaul and Maier reported that although the prognosis could be determined, this disease could not be diagnosed. However, the opposite situation is currently more likely.
The evolving definition and classification, rarity, and pooling of PAN and other vasculitides in clinical studies have complicated the formulation of evidence-based principles for PAN therapy.
Take-home messages
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Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis predominantly targeting medium-sized or small arteries. The pathogenesis remains enigmatic, although the clinical responses to immunosuppressive therapy support the concept that immunological mechanisms play an active pathogenic role.
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The spectrum of disease ranges from involving a single organ to polyvisceral failure. Any organ might be affected; however, for reasons that are not understood, PAN does not affect the lungs. In
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