Introduction
Polyarteritis nodosa (PAN) was first described by Kussmaul and Maier in 1866. The original and subsequent descriptions identified the pathological features of necrotizing arteritis with nodules along the walls of medium and small muscular arteries, affecting multiple organ systems throughout the body. Despite some overlap with smaller vessel disease, PAN is a distinct entity. Notably, the disease varies in its presentation from a relatively benign cutaneous form that may resolve without treatment to a severe systemic form that can be fatal. In this chapter, the systemic and cutaneous forms of PAN will be described under separate headings.
Polyarteritis Nodosa (Systemic)
Definitions and Classification Criteria
In the Chapel Hill Consensus Conference held for the nomenclature and definition of vasculitides, classical PAN was defined as necrotizing inflammation of medium- or small-sized arteries without vasculitis in arterioles, capillaries, or venules. PAN was separated from the distinct group of antineutrophil cytoplasmic antibody (ANCA)-associated microscopic polyangiitis (MPA), which was defined as necrotizing vasculitis with few or no immune deposits affecting small vessels. MPA is predominantly a renal disease and usually presents in childhood as rapidly progressive, crescentic, glomerulonephritis.
The widely accepted classification criteria for PAN have been the American College of Rheumatology (ACR) criteria, which were introduced in the 1990s and based solely on an adult registry. There have been two early attempts to introduce specific pediatric criteria for PAN, one by Ozen and colleagues in 1992 and one by Brogan and colleagues in 2002. These criteria were based on the pediatric practice and experience in children with PAN, although neither was tested for specificity, and there were no attempts at validation.
In 2006, the first unique childhood criteria for systemic PAN were published with the endorsement of the European League against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PRES), with the participation of the European Society of Paediatric Nephrology (ESPN) and the ACR. These criteria were established in two steps: initially, opinions were gathered from pediatric rheumatologists and nephrologists worldwide through a Delphi technique. Subsequently, the final criteria were agreed on in a consensus conference with 10 experts, using the nominal group technique. This was followed by a large validation exercise based on international Web-based registry for childhood vasculitides. The 2006 criteria were revised and validated based on this international registry and the consensus of an expert panel. After minor revisions, the final criteria with the highest sensitivity and specificity for childhood PAN were agreed upon; they are summarized in Box 34-1 . It should be emphasized that these are classification criteria and not diagnostic criteria, although they are often incorrectly used as such.
Evidence of necrotizing vasculitis in medium or small arteries or an angiographic abnormality showing aneurysm, stenosis, or occlusion of a medium- or small-sized artery (histopathology or angiography mandatory), plus one out of five of the following criteria:
- 1.
Skin involvement (livedo reticularis, skin nodules, or infarcts)
- 2.
Myalgia or muscle tenderness
- 3.
Hypertension (systolic/diastolic blood pressure greater than 95th percentile for height)
- 4.
Peripheral neuropathy (sensory peripheral neuropathy or motor mononeuritis multiplex)
- 5.
Renal involvement (proteinuria >0.3 g/24 hours or >30 mmol/mg of urine albumin/creatinine ratio on a spot morning sample; hematuria or red blood cell casts, >5 red blood cells/high-power field, red blood cell casts in the urinary sediment, or equal to 2+ on dipstick; or impaired renal function, measured or calculated glomerular filtration rate [Schwartz formula] <50% normal)
Epidemiology
There is currently a lack of data describing the epidemiology of childhood PAN; however, systemic PAN is generally considered the third most common systemic vasculitis encountered in children. In adults, at least in Europe and the United States, an estimated incidence ranges from 2 to 9 per million individuals per year. Childhood PAN seems to be of worldwide distribution, with no sex bias and with the majority of cases presenting in mid-childhood, although with a wide spectrum of ages affected.
In a multinational survey registering 110 childhood PAN patients (both systemic and cutaneous), the majority of respondents were from the eastern Mediterranean and South America. Because not all countries are represented in this survey, there is a certain bias involved, and future studies are needed to define whether there are true geographic or even ethnic differences. The majority of patients in another large case series of children with PAN in the UK were Caucasian (81%), 15% were Asian, and 2% were Afro-Caribbean.
Etiopathogenesis
The immunopathogenesis leading to vascular injury in PAN is probably heterogeneous. A number of infectious triggers have been implicated, and PAN-like illnesses have additionally been reported in association with cancers and hematological malignancies. However, associations between PAN and these infections or other conditions are rare in childhood. Streptococcal infection may be an important trigger, and indirect evidence suggests that bacterial superantigens may play a role in some cases. On the other hand, hepatitis B virus has been associated with PAN; however, this association has almost disappeared with recent vaccination protocols in children. The hepatitis B virus–associated PAN was an immune complex disease in which antiviral treatment was also required. In the revised 2012 Chapel Hill nomenclature, hepatitis B–associated PAN is classified under the “secondary vasculitis” category because there is a clear association with this virus.
In terms of pathogenic mechanisms it seems likely that the immunological processes involved are similar to those in other systemic vasculitides and include cell adhesion molecules, cytokines, growth factors, chemokines, neutrophils, and T and B cells. Of note, immunohistochemical studies performed on biopsied perineural and muscle vessels from homogeneous populations of PAN patients showed that inflammatory infiltrates consist mainly of macrophages and T lymphocytes, particularly of the CD8 + subset. To date, there is no reliable animal model of the disease. The PAN-like disease in cynomolgus macaques, which is very similar to the human disease, occurs only sporadically. Snyder et al. described a PAN-like illness arising spontaneously in beagle dogs, but to date this animal model has not provided insight to the pathogenesis of PAN in humans.
Genetic predisposing factors may make individuals vulnerable for developing PAN. Recently, an association of childhood PAN with mutations in the familial Mediterranean fever (MEFV) gene has been shown in Turkish children. This suggests that, at least in certain populations where the MEFV mutations are frequent, these mutations may be acting as one of the susceptibility factors for PAN. Additionally, there are reports of PAN occurring in siblings within families, which may add weight to the genetic hypothesis. Notably, mutations in the gene encoding adenosine deaminase 2 (ADA2) result in a syndrome of intermittent fevers, early-onset lacunar strokes, and other neurovascular manifestations; livedoid rash, hepatosplenomegaly, and systemic PAN-like vasculopathy have been recently described by two independent groups.
Clinical Features
Systemic PAN is characterized by constitutional symptoms such as malaise, fever (no specific pattern), weight loss, and a variety of different skin manifestations, diffuse myalgia, abdominal pain, arthralgia, and, on occasion, arthritis. Other clinical features including ischemic heart and testicular pain, renal involvement (hematuria, proteinuria, and hypertension), and neurological features (focal defects, hemiplegia, visual loss, mononeuritis multiplex, and organic psychosis) may occur.
Skin lesions are variable and may rarely resemble those of HSP but can also be necrotic and associated with peripheral gangrene ( Figs. 34-1 and 34-2 ). Livedo reticularis is also a characteristic feature, and occasionally fixed tender subcutaneous nodules overlying affected arteries are present in both upper and lower limbs. Skin infarctions may also be seen in this systemic form of the disease and can affect any part of the body. The clinical features at presentation for the largest reported cohort of systemic PAN (69 children) were as follows: fever (87%), myalgia (83%), skin (88%), renal (19%), severe gastrointestinal (GI) (10%), and neurological involvement (10%). Similar frequencies of clinical manifestations were recently reported in smaller studies from India and Croatia. If the diagnosis and prompt treatment are delayed, widespread infarction can occur in affected viscera ( Fig. 34-3 ). In some patients, rupture of arterial aneurysms can cause peritoneal bleeding with perirenal hematomata being a recognized manifestation of this phenomenon, particularly in patients with both PAN and familial Mediterranean fever ( Fig. 34-4 ).
The differential diagnosis of PAN depends on the spectrum of organ involvement. Other forms of vasculitis such as Kawasaki disease and secondary vasculitides need to be considered. Infections such as bacterial endocarditis with microembolism also need to be excluded. The autoinflammatory syndromes may also mimic certain features of PAN. The diagnosis of PAN can only be secured by a combination of histopathological demonstration of necrotizing vasculitis and/or radiological demonstration of aneurysms and other angiographic typical findings.
Laboratory Investigations
Leukocytosis and thrombocytosis are frequent, along with elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Mild anemia may occur as well. ANCA and antinuclear antibody (ANA) are typically negative in PAN. Recently, there has also been some interest in measurement of circulating endothelial microparticles and circulating endothelial cells as markers of endothelial inflammatory damage in PAN and other vasculitides, and circulating endothelial progenitor cells that might point to evidence of endothelial repair. Urinalysis findings may reflect renal arterial involvement. Proteinuria, hematuria, and even a decrease in renal function may occur.
Radiological Investigations
Demonstration of aneurysms reflecting the necrotizing vasculitis of renal, celiac, mesenteric, or arteries in other parts of the body is a part of the diagnosis ( Fig. 34-5 ). Brogan et a. have shown that changes other than aneurysms may also suggest a diagnosis of PAN. The most reliable nonaneurysmal signs were perfusion defects, the presence of collateral arteries, and delayed emptying of small renal arteries. The authors indicated that the sensitivity of the diagnosis of PAN increased with the presence of these features. If there is suspicion of cerebral vasculitis, cerebral arteriography may be required and can be done at the same examination. The dose of contrast agent administered requires careful consideration, particularly in small children. Conventional angiography remains the overall gold standard, though future progress in imaging may improve the sensitivity of noninvasive imaging. Magnetic resonance angiography (MRA) and especially computerized tomography angiography (CTA) have emerged as alternative, noninvasive techniques to delineate vasculitic lesions in PAN. However, MRA fails to detect small aneurysms or microaneurysms, although it can demonstrate large intrarenal and extrarenal aneurysms and stenosis or occlusions of the renal arteries or their branches, and areas of ischemia and infarction. Of note, MRA may overestimate vascular stenotic lesions, particularly in small children. CTA may also be able to reveal larger aneurysms and occlusive lesions and demonstrate areas of renal cortical ischemia and infarction, but concerns regarding the significant radiation exposure and its lack of sensitivity for the detection of vasculitic changes affecting smaller arteries in comparison to catheter arteriography limit its use.
