Polyarteritis nodosa and microscopic polyangiitis
Wegener granulomatosis (WG) is one of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) which also include microscopic polyangiitis (MPA, formerly called microscopic polyarteritis), Churg–Strauss syndrome (CSS) and so-called renal-limited vasculitis (previously referred to as idiopathic crescentic glomerulonephritis) .
Wegener granulomatosis is defined according to the Chapel Hill criteria as granulomatous inflammation involving the respiratory tract, with necrotizing vasculitis affecting small to medium-sized vessels (e.g. capillaries, venules, arterioles and arteries); necrotizing glomerulonephritis is common .
Wegener granulomatosis was first described by Friedrich Wegener in 1936, based on three similar autopsy cases. Nearly 20 years later, Godman & Churg named it the ‘Wegener triad’ . It is a multisystem disease affecting the ears, nose, larynx, eyes, lungs, kidneys, heart, joints, skin and central nervous system (CNS) . It is predominantly a disease of adults, usually 40–50 year olds, with a male-to-female ratio of 1.3–1.6 : 1. However, the disease does occur in children, and of the AAV occurring in the young, WG is seen most frequently .
The recently modified classification for WG requires the presence of three out of the following six criteria:
- renal involvement (proteinuria or haematuria or red blood cell casts)
- positive histopathology (granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area)
- upper airway involvement (nasal discharge or septum perforation, sinus inflammation)
- laryngo-tracheo-bronchial involvement (subglottic, tracheal or bronchial stenosis)
- pulmonary involvement (chest X-ray or CT scan)
- ANCA positivity (by immunofluorescence, ELISA PR3-ANCA or MPO-ANCA).
Sensitivity and specificity of these new EULAR/PRINTO/PRES criteria are 93% and 99% respectively for the differentiation of WG from other forms of vasculitis in the young .
The diagnosis of AAV can be challenging and ANCA undoubtedly play an important role. Davies et al. in 1982  described antibodies directed against antigenic determinants in the neutrophil cytoplasm of patients with segmental necrotizing glomerulonephritis. Methodological improvements for the detection of ANCA have resulted in increased sensitivity and specificity. Both indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) are used for routine diagnostic purposes. Typically, WG is associated with a cytoplasmic staining pattern of ANCA on IIF, and ELISA reveals specificity against proteinase 3 (PR3-ANCA). However, perinuclear ANCA (pANCA) with specificity directed against myeloperoxidase (MPO-ANCA) can also be found in patients with WG (Fig. 167.1). MPA and renal-limited AAV are typically associated with pANCA on IIF and MPO-ANCA on ELISA. Lastly, it should always be remembered that ANCA-negative forms of WG, MPA, renal-limited vasculitis and CSS are well described in children .
Other commonly observed non-specific findings include a mild normochromic normocytic anaemia together with a leucocytosis and thrombocytosis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently elevated. Raised immunoglobulins (polyclonal IgG) may also support the diagnosis, although this finding is not specific. Laboratory manifestations relating to renal involvement include dipstick haematuria and proteinuria, a raised protein creatinine ratio, raised serum creatinine and other associated laboratory features of renal failure.
The presence of ANCA (especially cANCA) has been found by some authors to be highly specific for WG, with up to 91% sensitivity and 98% specificity during active disease being reported in adults [7,8]. In children, there is also evidence to show a significant association with ANCA. In one report 10/12 patients had ANCA detected although only seven had the cANCA pattern on immunofluorescence . In subsequent reports, ANCA positivity was found in 59–95% [10,11]. It is likely that this range of ANCA positivity in children with WG reflects differences in age, variation in disease severity, and methodological differences in laboratory detection of ANCA between these two series. Whilst early reports by Van der Woude et al.  demonstrated the presence of these antibodies in adults with WG and correlated their presence with disease activity, more recent studies have questioned the usefulness of measuring ANCA to monitor disease activity  (see below).
Aetiology and Pathogenesis.
The most accepted model of pathogenesis proposes that ANCA activate cytokine-primed neutrophils, leading to bystander damage of endothelial cells and an escalation of inflammation with recruitment of mononuclear cells . However, other concomitant exogenous factors and genetic susceptibility appear to be necessary for disease expression as well.
The aetiology of ANCA generation in WG is unknown. It is clear that infections may precipitate the onset of the disease or relapses, perhaps inducing ANCA production by molecular mimicry . Genetic susceptibility to WG is probably polygenic . Whatever the mechanisms predisposing to ANCA generation, there is now good evidence that ANCA are directly involved in the pathogenesis of AAV. MPO-ANCA pathogenicity has been established in animal models  and in at least two cases of transplacental transmission in humans resulting in affected neonates [18,19].
Wegener granulomatosis is a necrotizing granulomatous vasculitis, predominantly affecting small arteries and veins, which are infiltrated with polymorphonuclear leucocytes followed by mononuclear cells. Granulomas are particularly seen in the upper and lower airways (Fig. 167.2), although there may be an absence of the classic histological changes, with the only abnormality being chronic inflammation. Renal lesions are variable; a focal and segmental glomerulonephritis is most commonly found although a diffuse proliferative glomerulonephritis with crescents is seen in those with a rapidly progressive clinical course and marked renal functional decline. Granulomas and evidence of vasculitis are often absent in renal biopsies. Skin biopsies may give supportive evidence for the diagnosis of WG. In a report of WG in a 10-year-old child, the finding of a leucocytoclastic vasculitis with organizing thrombi in the dermis and panniculus in the absence of granulomatous changes was typical of changes that are consistent with but not absolutely diagnostic of WG .
From a clinical perspective, it may be useful to think of WG as having two forms: a predominantly granulomatous form with mainly localized disease with chronic course, and a florid, acute small vessel vasculitic form characterized by severe pulmonary haemorrhage and/or rapidly progressive glomerulonephritis or other severe vasculitic manifestation (see below) . These two broad presentations may co-exist or present sequentially in individual patients.
The upper respiratory tract and ears are often affected first . Subacute or chronic otitis may cause mastoiditis; hearing loss can be secondary to serous otitis or sensorineural in origin. Nasal congestion and epistaxis are frequent and ulceration and crusting of the mucosa result from the underlying necrotizing inflammatory process that may lead to septum perforation. Chondritis of the nose results in the typical saddle nose deformity (Fig. 167.3) . Sinuses are often affected, ranging from mucosal thickening to pansinusitis and bone destruction. Oral features include jaw pain, gingival hyperplasia and palatal ulceration. Subglottic stenosis is the most commonly affected area in the tracheobronchial tree in children, affecting up to 48% of children (Fig. 167.4) [11,21]. In a child with stridor, laryngoscopy with biopsies of any lesions in the airway may be helpful diagnostically. Pulmonary involvement may be asymptomatic. Single or multiple nodular masses with or without cavitation may be seen, as can focal or diffuse infiltrates  (Fig. 167.5).
Reproduced from Brogan et al. Small vessel vasculitis. Pediatr Nephrol 2010;25:1025–35 with permission from Springer.
Clinical manifestations relating to renal involvement include hypertension, haematuria and/or proteinuria, nephritic and nephrotic syndrome, and in some cases a rapidly progressive nephritis with acute renal failure .
Coronary arteritis, myocardial infarction, granulomatous valvulitis of the aortic or mitral valves, pericarditis or pancarditis are all rare complications
Skin disease may present as erythema, urticarial lesions, petechiae, purpura, ulcerative lesions, pyoderma gangrenosum and necrotic lesions [11,20,25–33] (Fig. 167.6). In both paediatric and adult series, skin disease is reported in approximately 50% [4,11,21]. In one large series of 244 adults, 30 (14%) were found to have skin involvement and detailed clinical, histopathological and cANCA findings were reported . Initial presentation with skin disease is less common, occurring in 8.6–13% of cases [21,25,26]. No single lesion is pathognomonic and lesions must be considered together with other findings. One case report described a child presenting with nodular and necrotic acneiform lesions predominantly on her forehead, which then progressed to ulcers on the arms and buttocks  but at presentation, other features of WG were also identified.
Migratory arthralgias may affect several joints and symmetrical polyarthritis can occur but destructive arthritis is rare. Neurological involvement may result in cranial nerve palsies, mononeuritis multiplex, symmetrical peripheral neuropathy, cerebral infarction and transverse myelitis (Fig. 167.7). Ophthalmological disease causing conjunctivitis, episcleritis, corneoscleral ulcers, uveitis, vasculitis of the retina, optic neuritis and central artery occlusion is documented. Unilateral or bilateral proptosis may be caused by granulomatous pseudo-tumours of the orbit [34,35] (Fig. 167.8). Gastrointestinal symptoms are rare although vasculitic ischaemia may result in bowel perforation, and necrotizing vasculitic involvement of the anus and rectum has been seen (Fig. 167.9).
It is known that a limited form of WG also exists, in which the pathological findings are confined to the respiratory tract . Subglottic stenosis is a feature of WG that has been reported in the absence of other clinical markers but in association with ANCA, demonstrating the benefit of a laboratory marker that allows early diagnosis and intervention with appropriate treatment . A comparison of the clinical findings in children and adults is shown in Table 167.1.
In addition to the haematological and immunological investigations discussed above, radiology can be of diagnostic benefit in WG . Chest radiograph may demonstrate pulmonary infiltrates or discrete nodular and/or cavitating lesions; sinus radiographs may be abnormal and neck views may demonstrate subglottic stenosis [23,28].
Whilst the diagnostic value of ANCA is without question important, ANCA for the longitudinal monitoring of disease activity is probably unreliable for many patients with WG  although it can be used in some for this purpose (Fig 167.10). The reasons for this are not fully understood but are likely to include methodological limitations of ANCA detection, the partial dissociation of ANCA levels and disease activity associated with immunosuppressive therapy, and as yet undefined complexity in the exact role of ANCA in the pathogenesis of WG .
Renal morbidity and mortality are a major concern in WG and other AAV, so therapy aimed at preservation of renal function is a recurring theme for the treatment of WG in adults and children . Treatment for paediatric WG is broadly similar to the approach in adults, with corticosteroids, cyclophosphamide (usually 6–10 IV doses at 500–1000 mg/m2 per dose given 3–4 weekly; alternatively given orally at 2 mg/kg/day for 2–3 months) and plasma exchange (particularly for pulmonary capillaritis and/or rapidly progressive glomerulonephritis – ‘pulmonary-renal syndrome’) routinely employed to induce remission [5,39,40]. Intravenous pulsed cyclophosphamide is increasingly favoured over oral continuous cyclophosphamide in adults because of a reduced cumulative dose and less neutropenic sepsis  and it is therefore increasingly used to treat children with AAV as well, albeit without good paediatric evidence. This is followed by low-dose corticosteroids and azathioprine (1.5–3 mg/kg/day) to maintain remission [42,43]. Antiplatelet doses of aspirin (1–5 mg/kg once a day) could also be considered empirically on the basis of the increased risk of thrombosis associated with the disease process . Methotrexate may have a role for induction of remission in patients with limited WG  but is less commonly used as an induction agent in children with AAV. Co-trimoxazole is commonly added for the treatment of WG particularly in those with upper respiratory tract involvement, serving both as prophylaxis against opportunistic infection and as a possible disease-modifying agent . Recommendations regarding duration of maintenance therapy are based on adult trial data suggesting that the strongest predictor of relapse is withdrawal of therapy, indicating that maintenance therapy should be continued for several years . As a general therapeutic measure, prophylaxis against osteoporosis, gastrointestinal ulceration and infection (bacterial, and fungal) is a standard additional aspect of treatment for AAV .
As the use of cyclophosphamide contributes to morbidity and mortality [39,42], with infection playing a prominent role , and disease relapses occur in 50% of the patients with AAV as drugs are reduced or withdrawn, newer immunosuppressive agents and immunomodulatory strategies are being explored in both adults and children. Such treatments include mycophenolate mofetil (MMF) and rituximab, which have already been reported to be effective at inducing or maintaining remission in adults with AAV [48,49] and are currently being evaluated in randomized controlled trials (RCTs).
Increasingly, biological therapy is being used to treat children with small vessel vasculitis including AAV as well as ANCA-negative vasculitides. Agents used include rituximab (previously mentioned), anti-tumour necrosis factor (TNF)-α (etanercept, infliximab and adalimumab) and anakinra (recombinant interleukin-1 receptor antagonist) . These therapies are mainly reserved for those who have failed standard treatment or those patients in whom cumulative cyclophosphamide and/or corticosteroid toxicity is of particular concern. Other novel therapies for AAV are reviewed elsewhere .
Specialist localized treatment of the upper and lower respiratory tract involvement of WG is beyond the scope of this chapter; the reader is directed to the report of Hoffman et al.  and the recent report by White & Shah .
The AAV still carry considerable disease-related morbidity and mortality, particularly due to progressive renal failure or aggressive respiratory involvement, and therapy related complications such as sepsis.
The mortality for paediatric WG in one paediatric series was 12% over a 17-year period of study inclusion . The largest paediatric series of WG reported 40% of cases with chronic renal impairment at 33 months’ follow-up  despite therapy. Thus treatment has shifted WG from a disease associated with high mortality in the first year to that of a chronic illness associated with relapsing course and high renal morbidity during paediatric follow-up.
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Polyarteritis Nodosa and Microscopic Polyangiitis
Classic (macroscopic) polyarteritis nodosa (PAN) predominantly affects medium-sized arteries, and should be differentiated from the small vessel ANCA-associated vasculitis microscopic polyangiitis (MPA), which is now classified separately from PAN  but was historically referred to as ‘microscopic PAN’. Thus, for the purposes of this chapter, MPA and PAN will be described separately, although in reality there is a varying degree of overlap between these entities in some patients.
Microscopic polyangiitis (MPA, formerly microscopic polyarteritis) differs from classic PAN by the presence of extensive glomerular involvement, and may be defined as necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles); necrotizing arteritis involving small and medium-sized arteries may be present; necrotizing glomerulonephritis is very common; pulmonary capillaritis often occurs . Clinically, it can be difficult to distinguish from Wegener granulomatosis and often presents with rapidly progressive pauci-immune glomerulonephritis  in association with perinuclear antineutrophil cytoplasmic antibody (pANCA, MPO-ANCA) positivity .
Renal-limited AAV describes those with rapidly progressive glomerulonephritis, often with ANCA positivity (usually MPO-ANCA) but without other organ involvement, and probably represents a forme fruste MPA .
The typical clinical manifestations are rapidly progressive glomerulonephritis and alveolar haemorrhage. Other possible symptoms resemble those encountered in polyarteritis nodosa (see below). In adults, 75–80% of patients have pANCA/MPO-ANCA. MPO-ANCA pathogenicity has been established in animal models  and in at least two cases of transplacental transmission in humans resulting in affected neonates [6,7]. Renal limited forms are described in children and adults.
Treatment and Prognosis.
The treatment of MPA is similar to that previously described for WG, with corticosteroids and cyclophosphamide used for the induction of remission, followed by maintenance of remission with azathioprine. Plasma exchange should be considered for those with rapidly progressive glomerulonephritis [8,9] and newer agents, including mycophenolate mofetil and rituximab, are also increasingly used in children and adults .
For MPA in children, mortality during paediatric follow-up is reportedly 0–14% [11,12]. Two of seven children reported by Peco-Antic et al.  progressed to end-stage renal disease; one developed chronic renal failure and four normalized renal function. A selected population of 31 children with necrotizing pauci-immune glomerulonephritis and positive ANCA from Japan reported by Hattori et al. suggested a poor renal prognosis despite therapy . In that series, at 43 months’ follow-up, 29% developed end-stage renal failure, 19.4% had reduced renal function and only 48.4% had normal renal function. Using these data, the authors suggested overall 75% renal survival at 39 months, comparable to the poor renal prognosis of MPA in adults .
Polyarteritis nodosa (PAN) was first described in 1866 by Kussmaul and Maier in the autopsy of a 27-year-old man who had proteinuria, myalgia, neuritis and abdominal pain. It is a disease of small and medium-sized arteries with aneurysmal dilation, especially at arterial branching points. Although it is rare, PAN does occur in childhood [15–18]. There is a debate about the overlap of infantile polyarteritis with Kawasaki disease . Some of the early reports of infantile polyarteritis give classic descriptions of Kawasaki disease [20,21]. PAN may present as multisystem disease but there is also a group of patients in whom the cutaneous manifestations predominate and in whom the prognosis is considerably better [22–24].
In adults from Europe and the United States, the estimated annual incidence of PAN is 2–9/million . Although comparatively rare in childhood, it is the most common form of systemic vasculitis after Henoch–Schönlein purpura and Kawasaki disease [26,27]. However, the data are difficult to interpret since the incidence in various reports differs widely dependent on which criteria are used to classify patients into the PAN category. New criteria for the classification of PAN in children have recently been described (Box 167.1). Sensitivity and specificity of these new criteria were 73% and 100% respectively .
Box 167.1 New Criteria for the Classification PAN in Children
Histopathological evidence of necrotizing vasculitis in medium or small arteries or angiographic abnormality (aneurysm, stenosis or occlusion) as a mandatory criterion plus one of the following five:
- skin involvement (see below)
- myalgia or muscle tenderness
- peripheral neuropathy
- renal involvement
Aetiology and Pathogenesis.