PAN is a primary systemic necrotising vasculitis predominantly affecting the medium-sized vessels while sparing the arterioles, venules and capillaries. Historically the term was introduced as periarteritis nodosa in 1866 [1]. The American College of Rheumatology (ACR) criteria for PAN were first described in 1990 and, though have an 80 % sensitivity and specificity in adults, have not been validated for childhood PAN [2].

The Chapel Hill nomenclature criteria of 1994 include two separate headings: classic PAN or microscopic polyangiitis [3]. The more recent EULAR/PReS criteria have been derived from the modified Chapel Hill classification (Table 37.1) [4]. The EULAR/PReS criteria are 73 % sensitive and 100 % specific for childhood PAN [5].

PAN is rare in the pediatric population and has no sex predilection. It has peak age of onset round 10 years of age [6, 7]. In 2004 Ozen et al. described 110 children with childhood polyarteritis nodosa. These children could be classified into four categories: classic PAN associated with hepatitis B antigen, cutaneous PAN, systemic PAN and microscopic polyarteritis of adults. Systemic PAN formed 57.2 % of this cohort. The presence of HbsAg-associated PAN was less than 5 % cases. In the largest series from 21 hospitals, no seasonal variation was found [7]. In a nationwide survey of childhood vasculitides done in Turkey, Ozen et al. found childhood PAN to be the third most common primary vasculitis affecting children, Henoch-Schonlein purpura being the most common at 81 % [8].

Less than 10 % cases of childhood PAN are hepatitis B virus (HBV) related. With universal immunisation against hepatitis B, the incidence of HBV-related PAN is declining rapidly from 60 % in pre-immunisation era to 7 % in the post-HBV vaccination era [9]. Streptococcus infection has also been linked to PAN more so to cutaneous PAN. Superantigens can cause immune activation as evidenced by skewing of the Vβ repertoire. Though often implicated in HSP and Kawasaki disease, it has been less commonly seen both in adult and childhood PAN [10, 11]. Recently, deficiency of adenosine deaminase 2, due to loss of function mutation in the CECR1 (cat’s eye syndrome chromosome region, candidate 1), has been found to be associated with familial PAN and infantile strokes [12, 13].

The fibrinoid necrotising inflammation of medium and small vessels is a characteristic of PAN, is composed of neutrophils initially and is later predominated by macrophages and lymphocytes. This inflammation and transmural fibrinoid necrosis result in pseudoaneurysms that are felt as arterial nodules and thus the name polyarteritis nodosa [14]. The eddy currents caused by the aneurysms result in thrombi formation. The healing of the vessel wall takes place by fibroblast proliferation that leads to wall thickening and produces areas of stenosis or occlusion that cause the multiple small infarcts seen in this disease [15].

Constitutional symptoms of fever, fatigue and weight loss are present in more than 95 % of the children [7]. The non-specific nature of these complaints often leads to a delay in diagnosis until some more specific features such as skin involvement or hypertension develop. Cutaneous involvement such as skin infarctions, tender subcutaneous nodules and livedo reticularis is reported in 86–90 % cases of systemic PAN at onset (Fig. 37.2) [7, 16]. Myalgias are present in more than 70 % of the children at onset. Up to 1/3 children may present with CNS involvement and 10–15 % may present with pulmonary and cardiac involvement [7]. In the study of 36 children of systemic PAN, 11.5 % had hypertension at onset, whereas 22.8 % developed it over the course of the disease [16]. Livedo may occur with or without ulceration, and rarely ulceration and gangrene of the tips of digits and penis may occur because of end artery involvement [17]. Gastrointestinal symptoms of pain in the abdomen and vomiting are often the presenting problem in a child and occur probably due to mesenteric ischaemia. Perforation of the bowel secondary to ischaemia can also be present [18].

Nervous system involvement (both peripheral and central) has been reported in up to 30 % of the children at onset [16]. Mononeuritis multiplex is commonly seen; focal defects, hemiplegia, visual loss and rarely organic psychosis can also be present [19, 20].

Microscopic polyangiitis (MPA) though rare in children remains an important differential for systemic PAN. MPA is associated with rapidly progressive glomerulonephritis, lung involvement and Anti Neutrophilic Cytoplasmic Antibody (ANCA) positivity features rarely seen in PAN [21]. Infection-associated vasculitides secondary to viruses like hepatitis B, hepatitis C and HIV need to be ruled out. HBV-associated PAN is now considered as a separate entity and is classified as a secondary vasculitis.

Tissue biopsy demonstrating necrotising inflammation involving a medium artery and angiogram demonstrating aneurysms of medium and small muscular arteries are the commonly used tests for diagnosis. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are characteristically elevated in these children. Urinary abnormalities like proteinuria and haematuria are seen in about one third of patients [7].

Imaging is an important modality for the diagnosis of childhood PAN, and demonstration of aneurysms in medium-sized vessels by angiography is one of the mandatory criteria for diagnosis. CT angiography is the first modality to detect aneurysms, but in almost one third a conventional angiography might be required. Renal and mesenteric arteries are predominantly involved [22]. The sensitivity of diagnosing PAN is 43 % in the presence of aneurysms. This increases to 80 % when non-aneurysmal changes like perfusion defects, collateral artery formation, delayed emptying of small renal vessels and beaded tortuosity are present [22]. The renal arteries are affected in more than 80 % cases with GI tract and hepatic arteries involved in more than 50 % cases. The small intestine and mesentery are most commonly affected, followed by the colon [23]. MR angiography is able to pick up larger aneurysms but may miss small aneurysms and other non-aneurysmal signs of medium-vessel vasculitis [24, 25]. Tc-99 m dimercaptosuccinic acid (DMSA) scan of the kidneys can provide an indirect evidence as patchy areas of decreased isotope uptake may appear in the renal parenchyma due to medium-vessel vasculitis [26].

Corticosteroids, both oral and intravenous, form the mainstay of treatment of this disease. The use of cyclophosphamide as reported by Fauci et al. in 1979 probably changed the way PAN is now treated worldwide [27]. This led to a favourable outcome and no residual disease after 2–3 years of disease onset [28]. In the multicentre study by Ozen et al., two thirds of children received cyclophosphamide. Azathioprine was the drug used in one third of children. Five to ten percent were given cyclosporine or methotrexate after cyclophosphamide. IVIG was used in 10 % of cases [7]. Oral cyclophosphamide in a dose of 2 mg/kg/day for 2–3 months has been used, or pulse intravenous cyclophosphamide for 6 months or less can also be used. Low-dose aspirin is also recommended [29]. Azathioprine is used for maintenance up to 18 months. Methotrexate, cyclosporine and mycophenolate mofetil have also been used for this condition [30]. Plasma exchange can be considered in severe cases especially with renal involvement [31]. Recently, the successful use of rituximab, anti-CD20 blockade, has also been reported for resistant cases. TNF inhibitor, infliximab, has been used in severe cases resistant to cyclophosphamide and rituximab [30, 32–34]. In a multicentre study, 11 children with PAN were given a biological agent, infliximab was given to 7, of which one was switched to rituximab, and one was given adalimumab. Five children were given rituximab and one was given etanercept. The biological medications were used for severe, organ/life-threatening disease not responding to 1 mg/kg/day of systemic steroids and cyclophosphamide [30, 35]. Cyclophosphamide use in pediatric population can add to risk of infections, infertility and malignancies. Mycophenolate mofetil has not been used extensively for the treatment of PAN and a trial; MYPAN which is a non-inferiority trial comparing mycophenolate mofetil to cyclophosphamide is currently ongoing [36].

In adults with PAN, the 5-year mortality is determined by the FFS (five factor score). This has five factors as the name suggests: proteinuria >1 g/day, renal insufficiency (creatinine >140 μmol/L), cardiomyopathy, gastrointestinal manifestations and central nervous system (CNS) involvement. Five-year mortality with FFS = 0 was 12 % and increased to 46 % with an FFS of >2 [37]. The authors suggested a combination of cyclophosphamide and corticosteroids for patients with a higher FFS. The FFS has since been modified to include ENT involvement for patients with granulomatous polyangiitis which has a score of -1 as it is associated with a good prognosis [38, 39]. These prognostic factors have not been validated in children with PAN.

Relapses are uncommon in systemic PAN and it is usually a monophasic disease. Less than 10 % of the children experience a relapse over a period of 5 years. Mortality is rare in children and is reported to be around 1 % [7]. Relapses and mortality due to renal and cardiac causes were reported before the use of cyclophosphamide [6, 40]. In a multicentre study of 52 children with childhood PAN (both systemic and cutaneous), 36 children of systemic PAN were included. Fifty percent of the children with systemic PAN had clinical remission, 28 % had clinical remission on medication, 16.7 % of the children relapsed, and the mortality reported from this cohort was 3.8 % [16]. Children with PAN in remission have features to suggest risk factors for premature atherosclerosis [41, 42]. Thus, a long-term follow-up of these children is required. Demirkaya et al. validated the use of Birmingham Vasculitis activity Score (BVAS) in childhood primary systemic vasculitides including PAN and found moderate correlation with physician global disease assessment score and a low correlation with acute phase reactants, ESR and CRP [43].