Polyarteritis Nodosa

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, sometimes in association with pulmonary capillaritis.

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 et al. in 1992 and one by Brogan et al. 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 Pediatric 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. The European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) consensus guidance on diagnosis and management of pediatric vasculitides also endorsed these criteria.

Epidemiology

There is currently a lack of data describing the epidemiology of childhood PAN. 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 gender bias (although pediatric literature suggests a higher incidence in girls) and with the majority of cases presenting in mid-childhood (9 to 10 years old), 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 were represented in this survey, there is a certain bias involved, and future studies are needed to define whether there are true geographical or even ethnic differences. The majority of patients in another large case series of children with PAN in the United Kingdom were Caucasian (81%); 15% were Asian and 2% were Afro-Caribbean.

Etiology and Pathogenesis

The immunopathogenesis leading to vascular injury in PAN is probably heterogeneous. A number of infectious triggers have been implicated (parvovirus B19, cytomegalovirus [CMV]), 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 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 to developing PAN. An association of childhood PAN with mutations in the Familial Mediterranean Fever (FMF) ( 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. ^, The condition is referred to as deficiency of adenosine deaminase 2 (DADA2) and is described in more detail later in this chapter.