Update in paediatric vasculitis

Best Practice & Research Clinical Rheumatology 23 (2009) 679–688

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Update in paediatric vasculitis ¨ zen, Professor of Pediatrics a, Robert C. Fuhlbrigge, Associate Professor Seza O of Pediatrics and Dermatology b, * a

Department of Pediatrics, Hacettepe University, Ankara, Turkey Program in Pediatric Rheumatology, Division of Immunology, Children’s Hospital- Boston, 300 Longwood Ave., Boston, MA 02115, United States b

Keywords: paediatric rheumatology vasculitis/classification vasculitis/pathogenesis vasculitis/diagnosis polyarteritis nodosa Wegener granulomatosis microscopic polyangiitis Henoch Scho¨nlein purpura Kawasaki disease primary angiitis of the central nervous system Takayasu arteritis Churg–Strauss syndrome anti-neutrophil cytoplasmic antibodies

Vasculitis refers to a heterogeneous group of disorders that are characterised by inflammatory destruction of blood vessels. Although simple to define, almost nothing about vasculitis is simple. From classification to diagnosis, and from pathogenesis to management, large gaps remain in our understanding. Despite extensive and ongoing research, the fundamental mechanisms underlying the initiation and continuation of systemic vasculitis remain poorly understood. Thus, vasculitis continues to provide tremendous challenges to both clinicians and investigators and remains a rich source of issues for discussion. This review concentrates on recent changes proposed for the classification of paediatric vasculitis and advances in the concepts of aetiopathogenesis. Availability of improved classification criteria for children should prompt planning for multicentre-controlled studies for the treatment of these rare but important diseases. Ó 2009 Elsevier Ltd. All rights reserved.

New concepts in classification The classification of vasculitides has been controversial since the first attempts more than a century ago due, in large part, to a general lack of understanding regarding the mechanisms of disease

Abbreviations: American College of Rheumatology, ACR; Anti-neutrophil cytoplasmic antibodies, ANCA; C-reactive protein, CRP; Churg–Strauss syndrome, CSS; European League Against Rheumatism, EULAR; European Vasculitis Study, EUVAS; Henoch–Schonlein purpura, HSP; Intravenous immunoglobulin, IVIG; Kawasaki disease, KD; Microscopic polyangiitis, MPA; Myeloperoxidase, MPO; Paediatric Rheumatology European Society, PRES; Polyarteritis nodosa, PAN; Primary angiitis of the central nervous system, PACNS; Proteinase-3, PR3; Pulse intravenous methylprednisolone, IVMP; Takayasu arteritis, TA; Tumour necrosis factor, TNF; Wegener granulomatosis, WG. * Corresponding author. Tel.: 617 525 8502; Fax: 617 264 5123. ¨ zen), [email protected] (R.C. Fuhlbrigge). E-mail addresses: [email protected] (S. O 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.07.004

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pathogenesis [1]. Most current classification systems are based on a combination of histological and clinical features. A consensus committee convened by the American College of Rheumatology (ACR) in 1990 proposed classification criteria based on adult data [2]. The ACR Vasculitis Study Committee, however, limited itself to defining ‘primary’ vasculitis characteristics and only considered seven types of vasculitis. These, and the classification systems proposed by Lie [3] and by the Chapel Hill consensus conference [4] in 1994, have formed the basis of current practice. These systems are not designed for diagnosis of vasculitis, but as entry criteria for research studies. They omit important clinical forms of vasculitis and are, in general, inadequate for clinical application. The fact they were developed based on adult data alone is also a drawback for paediatric practice. As new data emerge in vasculitis, as in other complex medical syndromes, conditions previously thought to be similar turn out to differ in fundamental ways and conditions previously thought to be separate are found to share pathogenic mechanisms. For example, polyarteritis nodosa (PAN) classically refers to a medium-sized muscular arteritis. Although most cases involve both visceral and cutaneous vessels, disease limited to skin (cutaneous PAN), or involving the eyes and inner ears (Cogan’s syndrome), have been described [5]. The identification of PAN patients with anti-neutrophil cytoplasmic antibodies (ANCAs) to myeloperoxidase (MPO) has led to the addition of ANCA-positive microscopic PAN to the list of variants [6]. The result is that use of the term PAN today refers to a broad array of conditions, some of which are limited – others systemic, some benign and others life-threatening. Clearly, any classification system will require modification as knowledge advances. Unfortunately the tools for doing so in a coherent manner for vasculitis have remained elusive. An International Consensus Conference, formed with the support of European League against Rheumatism (EULAR) and the Pediatric Rheumatology European Society (PRES), met in 2006 and proposed the first true paediatric classification scheme (Table 1) [7]. Using standard consensus techniques, the classification committee tried to incorporate recent advances in diagnostic imaging and current knowledge regarding pathogenesis of specific disorders. For example, the presence of IgA immune complexes in biopsy material has been suggested as a part of the criteria for Henoch–Schonlein purpura (HSP), and ANCA have been included as a diagnostic feature of WG. The proposed criteria for HSP, PAN and Wegener granulomatosis (WG) have been validated and updated by an international consensus

Table 1 Classification of childhood vasculitis (Adapted from EULAR/PReS endorsed criteria for the classification of childhood vasculitides (7)). I Predominantly large-vessel vasculitis  Takayasu arteritis II Predominantly medium-sized vessel vasculitis  Childhood polyarteritis nodosa  Cutaneous polyarteritis  Kawasaki disease III Predominantly small vessels vasculitis (A) GRANULOMATOUS  Wegener’s granulomatosis  Churg–Strauss syndrome (B) NON-GRANULOMATOUS  Microscopic polyangiitis  Henoch–Scho¨nlein purpura  Isolated cutaneous leukocytoclastic vasculitis  Hypocomplementemic urticarial vasculitis IV Other vasculitides  Behçet disease  Vasculitis secondary to infection (including hepatitis B associated polyarteritis nodosa), malignancies, and drugs, including hypersensitivity vasculitis  Vasculitis associated with connective tissue diseases  Isolated vasculitis of the central nervous system  Cogan syndrome  Unclassified

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Table 2 Henoch Schonlein purpura (adapted from EULAR/PReS consensus criteria (9)). Mandatory Criteria: presence of purpura or petechiae with a lower limb predominance, plus 1 out of 4 of the following criteria: 1. Abdominal pain 2. Histopathology showing typical leukocytoclastic vasculitis with predominant IgA deposit or proliferative glomerulonephritis with predominant IgA deposit 3. Arthritis or arthralgia 4. Renal involvement (proteinuria or hematuria or presence of red blood cell casts) Purpura with atypical distribution require demonstration of IgA on a tissue biopsy.

Table 3 Polyarteritis Nodosa Criteria (adapted from EULAR/PReS consensus criteria (10)). Mandatory Criteria: Histopathology (evidence of necrotising vasculitis in medium or small sized arteries) or angiographic abnormality (Angiography showing aneurysm, stenosis or occlusion of a medium or small sized artery, not due to fibromuscular dysplasia, or other non-inflammatory causes) plus 1 out of 5 of the following criteria: 1. Skin involvement: livedo, skin nodules or infarctions 2. Myalgia or muscle tenderness 3. Hypertension 4. Peripheral neuropathy (sensory or motor) 5. Renal involvement (proteinuria, or hematuria or impaired renal function)

committee in conference in Ankara in 2008 [8–10] (Tables 2–4). However, given our lack of true understanding with regard to molecular pathogenesis, classification will remain an imperfect science. These dilemmas are highlighted by the following case presentation. A 10-year-old girl presented with fever, myalgia and a maculopapular rash along with skin nodules and severe inflammation of the tongue and uvula. She subsequently developed ischaemia and discolouration of the tips of three fingers and was admitted to a local hospital. A biopsy of the skin showed necrotising vasculitis of medium-sized vessels. Steroids were started along with prostacyclin (Iloprost) and volume expansion. Her erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were very high. The inflammation of the mouth progressed to include the necrosis of the soft palate and uvula. She was referred to a tertiary hospital where further examination revealed bilateral sinusitis and continued high acute-phase reactants. A biopsy of the palate and nasal mucosa was done for diagnosis and to rule out mycotic disease. There were no granulomas on biopsy. Enzyme-linked immunosorbent assay (ELISA) for PR3 and MPO ANCA was reported as negative although she had mild, non-specific staining on indirect immunofluorescence. A diagnosis of PAN was made and pulse cyclophosphamide was added to highdose corticosteroid treatment. In the fourth week of hospitalisation she was noted to have proteinuria and haematuria. Her serum creatinine showed a slow progressive increase. The family refused a renal biopsy. She also developed dyspnoea and a chest X-ray revealed probable pulmonary haemorrhage. She was started on pulse methylprednisolone and plasmapheresis, and monthly intravenous (IV) cyclophosphamide was switched to daily oral therapy. Her pulmonary symptoms and renal findings gradually improved. At the time of discharge 10 weeks later, she had residual discolouration of her finger tips and a nasal speech quality due to loss of the uvula. She had normal laboratory findings, including acute-phase reactants, and returned to school and normal daily activities. Based on the current and proposed criteria, this patient not only meets the requirements for diagnosis of PAN (biopsy-proven necrotising vasculitis and both skin and renal involvement) but also presents with pulmonary/renal/upper airway involvement suggestive of WG (see Tables 2 and 3). This makes interpretation of the literature for support of specific therapeutic strategies very difficult. Is there biological evidence to support a distinction between Wegener granulomatosis and microscopic polyangiitis? As highlighted in many case studies, the classification of WG is hampered by overlap with microscopic polyangiitis (MPA), and vice versa. In general, these two diseases do have distinct clinical

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Table 4 Wegener Granulomatosis Criteria (adapted from EULAR/PReS consensus criteria (8)). Diagnosis requires the presence of 3 out of 6 of the following criteria: 1. Renal involvement: Proteinuria or hematuria 2. Histopathology: Granulomatous inflammation 3. Upper airway involvement: Epistaxis, crusts, granulomata, nasal septum deformity, recurrent or chronic sinus inflammation 4. Laryngo-tracheo-bronchial involvement: Subglottic, tracheal or bronchial stenosis 5. Pulmonary involvement: Chest X ray or CT showing the presence of nodules, cavities or fixed infiltrates 6. Presence of ANCA

features [11]. However, as in our case above, patients may lack the typical features of the disease and fall into a diagnostic grey zone. There is some biological evidence that WG and MPA are different entities [12]. We already know that WG is mainly associated with PR3-ANCA, whereas the main target of ANCA in MPA is MPO. A number of specific polymorphisms have been associated with the development of PR3-ANCA versus MPO-ANCA. Alpha-1 anti-trypsin is the physiological inhibitor of PR3 and carriage of the defective allele PI*Z was reported as the first genetic risk factor for the development of PR3-ANCA-associated vasculitis [13]. MPO-ANCAs have also been shown to produce glomerulonephritis and vasculitis in a mouse model, thus providing definitive experimental evidence that MPOANCAs are pathogenic [14]. None of the ANCA animal models developed to date, however, has reproduced the granulomatous vasculitis typical of WG. Further evidence supporting a difference in pathogenesis lies in the identification of single nucleotide polymorphisms (SNPs) in the adhesion protein CD18 that associates with MPO-ANCA, but not PR3-ANCA [13]. It is probable that genetic studies will provide more substantial understanding for the difference of MPA, WG and CSS. It is only after we know more about the molecular mechanisms involved that we will be able to justify our classification strategies and improve them. New concepts in pathogenesis Despite extensive and ongoing research, the fundamental mechanisms underlying the initiation and continuation of systemic vasculitis remain poorly understood [15]. Theories of pathogenesis run the gamut of immunologic mechanisms, with more or less evidence for application in specific syndromes. Proposed mechanisms include humoral factors (e.g., pathogenic auto-antibodies in ANCAassociated vasculitis), immune complex formation (e.g., IgA in HSP and cryoglobulinemic vasculitis), auto-reactive T cells and altered recruitment of leucocyte populations to vessel walls (e.g., macrophages in Kawasaki disease (KD) and eosinophils in CSS). Considerable interest remains in infectious causes or triggers for paediatric vasculitis, particularly with regard to KD and HSP. Although the cause of KD remains unknown, it has many unique pathological features that suggest it is caused by a transmissible agent. Increased macrophages and IgA-producing plasma cells, as well as unusual cytoplasmic inclusion bodies, have been described in the vessel walls and bronchial epithelium of KD patients relative to controls [16]. The significance of these findings is unclear, but one interpretation is that a specific respiratory pathogen may be associated with KD. Reports indicating that specific viruses (e.g., Epstein–Barr virus, parvovirus and HIV-2) or bacterial toxins (e.g., streptococcal erythrogenic toxin and staphylococcal toxic shock toxin) account for a majority of cases, however, have not been substantiated [16]. This has led to the speculation that KD represents infection with an unknown pathogen or, perhaps more likely, a final common pathway of immune-mediated vascular inflammation following a non-specific inciting infection. A wide variety of infections have also been associated with HSP. Group A streptococcus is a common precipitant, with evidence for recent infection in up to one-third of cases, but exposure to Bartonella, Haemophilus parainfluenza and numerous vaccines and drugs have also been reported to precede the development of HSP [17]. Genetic studies have only recently been applied to questions in paediatric vasculitis, though this is likely to be a strong area of interest in the coming years. A recent large genome-wide association study in KD has identified a number of highly significant SNP associations validated in a separate population and confirmed by fine mapping [18]. A separate study of CRP and tumour necrosis factor (TNF) alleles

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also identified an association of specific genotypes with incidence of KD [19]. It is hopeful that functional correlation of these variants will lead to improved susceptibility and aneurysm risk assessment in KD. A recent study from Turkey reports a high frequency of heterozygous MEFV mutations in patients with PAN and no history or symptoms of familial Mediterranean fever [20]. Patients with mutations were both younger, had more extended symptoms (e.g., oedema and arthritis) and elevated levels of ESR and CRP. This adds to the impression that dysregulation of the inflammasome is an important and common susceptibility factor in rheumatic diseases. Diagnosis As highlighted by the discussion above, one of the primary issues in management of vasculitis is the difficulty in establishing a diagnosis [11]. Early in the course of disease, findings are often non-specific and reflect systemic inflammation (e.g., fever, malaise and elevated acute-phase reactants). As vessel damage progresses, more characteristic abnormalities of vascular injury will accumulate including clinical evidence (e.g., pulseless extremity, hypertension and nailfold capillary changes), biochemical evidence (e.g., elevation of von Willebrand factor antigen or pentraxin) and characteristic auto-antibodies (e.g., ANCA and anti-endothelial antibodies). While these features may be highly characteristic of vasculitis, they are not typically included in routine screening examinations. Pathognomonic changes (e.g., infarct, aneurysm, pulmonary or gastrointestinal haemorrhage) commonly reflect severe and often irreversible tissue injury. Although much effort has been directed towards identification of improved diagnostic studies and biomarkers, there are no highly sensitive and specific measures defined for any of the primary vasculitic disorders. Clinical A detailed physical examination of the skin and vascular structures remains the most useful diagnostic measure. Nailfold capillary examination and retinal vessel inspection can provide significant supporting evidence of vessel injury and should be included in any evaluation of patients without an established diagnosis. Pulmonary function testing with an elevated diffusing capacity can establish a high index of suspicion for pulmonary haemorrhage. Imaging Advances in quality and special sequences have improved the reliability of imaging studies, but they remain most useful to monitor disease or confirm a clinical suspicion rather than as screening studies [21]. Although echocardiogram evidence of coronary artery ectasia has been used as a guide to therapy for KD, a recent study has shown that similar and transient coronary artery changes can be identified in patients with systemic juvenile idiopathic arthritis (JIA) or other significant systemic inflammatory diseases, thus diluting its value [22]. MRI- and CT-based arteriograms and venograms can provide good resolution of large- and medium-sized vessels and have become the standard for evaluation of Takayasu arteritis (TA) and monitoring of established disease, but the standard for evaluation of smaller vessels, such as of PAN, remains the conventional angiogram. Laboratory studies With the exception of KD, the reference standard for diagnosis of vasculitis remains histopathological demonstration of vascular injury on tissue biopsy [11]. Again, a biopsy is seldom needed for HSP. Decisions to biopsy are relatively easy when characteristic lesions are readily available (e.g., skin), but become more difficult when the involved areas are relatively inaccessible (e.g., central nervous system) or when investigating internal organs that may already show vascular compromise. Other blood and tissue studies can provide important supporting evidence, or rule out infectious or malignant conditions in the differential diagnosis, but are not in themselves diagnostic. Initial evaluation of patients with suspected vasculitis typically includes a complete blood count, measures of acute-phase reactants (e.g., ESR and CRP) and screening liver and renal function studies. The von Willebrand factor antigen is

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released by damaged vascular endothelium and is therefore elevated in small-vessel vasculitis. It is similarly released, however, in other vascular injury disorders that may be in the differential diagnosis, including trauma, stroke and severe infections. Other markers of endothelial cell function (soluble selectins and thrombomodulin, pentraxin, circulating endothelial cells, endothelial microparticles, etc.) show promise as more sensitive and specific measures of vessel health, but remain research tools at the present time [23]. Once a diagnosis is established, patients can be followed with studies directed towards their specific needs. The availability of serologic testing for ANCA has shown it can be of substantial value in assessment of patients with possible ANCA-associated vasculitis. ANCA testing should be carried out both with indirect immunofluorescence and ELISA testing for PR3 and MPO. Nominally, the findings in paediatric patients are similar to those in adults, with a high correlation between the identification of PR3-ANCA (c-ANCA) and the diagnosis of WG and the identification of MPO-ANCA (p-ANCA) in patients with microscopic polyangiitis. Management of childhood vasculitides Regarding prognosis and therapy, there is a general lack of controlled multicentre trials for even the most common childhood vasculitides. In the absence of adequate paediatric-specific information to direct care in children, paediatric rheumatologists depend mainly on studies of adult rheumatology for recommendations regarding the treatment of systemic vasculitides, including PAN and WG. The European Vasculitis Study (EUVAS) group was established to design controlled studies in adult vasculitides that would provide Level 1 evidence. Over the past 5 years, this group has completed and published a number of high-quality trials comparing therapeutic regimens in adult patients (e.g., CYCAZAREM, NORAM, MEPEX and CYCLOPS studies [24]). The reader is referred to the EUVAS website (http://www.vasculitis.org/comptrials.htm) and the recently published EULAR recommendations for the management of small-, medium- and large-vessel vasculitis in adults [25,26]. There has, however, been substantial improvement in survival of both adult and paediatric patients with systemic vasculitis over the past several decades associated with the use of immunosuppressive therapies [27]. It is beyond the scope of this article to review the management of pediatric vasculitis in detail. In the following paragraphs we highlight only some of the more recent studies and changes in standards of practice. Henoch–Scho¨nlein purpura HSP remains largely a clinical diagnosis (Table 2) [9]. Biopsy is indicated only when the purpura are not typical and the diagnosis remains in question. In general, long-term outcomes in HSP are quite good, with a major exception involving patients with significant kidney disease. The use of prednisone in HSP has continued to be controversial, though some data are now available. A randomised placebocontrolled study of 40 children with HSP showed that early prednisone therapy in HSP did not reduce the risk of renal involvement at 1 year [28]. A subsequent double-blind placebo-controlled study of early prednisone in 171 patients with HSP showed that prednisone did not prevent development of renal involvement, but was effective at reducing renal and extra-renal symptoms if present [29]. Of two recent meta-analyses, however, one supported the use of corticosteroids, indicating reduced odds of developing persistent renal disease as well as reduced odds of both surgical intervention for and recurrence of abdominal pain [30], while the other did not, showing no significant difference in the risk of persistent kidney disease in children treated with prednisone [31]. A short course of prednisone is probably indicated to prevent intussusception in patients with severe gastrointestinal involvement [29], but we do not have Level I evidence to guide treatment of arthritis or severe kidney disease [32]. Renal biopsy is useful for confirming the extent and severity of nephritis and planning treatment; the development of end-stage renal disease being associated with a higher percentage of glomeruli with crescents and the degree of proteinuria [33]. Nailfold capillary abnormalities have been reported to persist well after clinical symptoms remit, suggesting that subclinical vasculitis may be present longer than might otherwise be apparent [34].

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Kawasaki disease Although clinical standards for evaluation of classic KD are broadly accepted, it has become increasingly recognised that children who do not meet the criteria may have an incomplete or atypical form of KD [35]. A particularly high level of suspicion is needed in infants younger than 1 year as they are the group most likely to develop coronary artery aneurysms. KD should be considered in any infant or young child with persistent, unexplained fever even if principal clinical criteria are lacking. Intravenous immunoglobulin (IVIG) continues to offer a remarkable combination of efficacy and safety for the treatment of KD [35]. Therapy within the first 10 days of illness reduces the incidence of coronary artery aneurysms by more than 70% and rapidly restores disordered lipid metabolism and depressed myocardial contractility. In contrast, studies have not demonstrated long-term benefit from the use of aspirin, though it is still an element of standard therapy during the acute febrile phase and the first weeks to months following diagnosis [36]. Use of corticosteroids has been controversial in KD, despite their clear value in all other forms of vasculitis [11]. A randomised trial of initial therapy with pulse intravenous methylprednisolone (IVMP) (30 mg kg 1) plus IVIG versus IVIG alone did not show a benefit of pulse steroid therapy in the early acute phase [37], although a recent non-randomised study has shown benefit [38]. Increasing interest has been applied to cases resistant to standard therapy. Persistent or recurrent fever after IVIG therapy usually indicates ongoing vasculitis, with increased risk of developing coronary artery aneurysms [35]. While not established by prospective studies, a number of clinical reports support the treatment of children who have not responded to IVIG and still have active KD with one to three daily doses of IVMP (30 mg kg 1) [39]. Other immunosuppressive therapies, including infliximab, may also be beneficial, although randomised clinical trials are lacking [40]. In summary, with modern treatment and cardiologic follow-up, the prognosis of children with KD is excellent. Long-term follow-up of children without persistent coronary artery abnormalities in Japan has demonstrated no increase in morbidity or mortality after 25 years [41]. However, a recent report indicating a rise in IVIG-resistant KD in one well-defined clinical population may be a signal that new issues could arise in the care of KD patients [42]. ANCA-associated vasculitis (Wegener granulomatosis (WG) and Microscopic polyangiitis (MPA) and Childhood PAN) For ANCA-associated vasculitides, MPA and WG, the EULAR recommendations for adult patients (Tables 3 and 4) outline the treatment with high levels of evidence from controlled studies [8,10]. For induction of remission in adults, corticosteroids and cyclophosphamide (oral or IV) are indicated for both WG and MPA. For remission maintenance therapy, both azathioprine and methotrexate have been shown to be effective. PR3-ANCA is positive in most paediatric patients with WG, as in adults. Although this auto-antibody is highly specific in adults, it may be found in other diseases (e.g., cystic fibrosis) which are more common in children. Accordingly, in children, a positive ANCA titre is supportive but should not replace a tissue biopsy in confirming the diagnosis of WG, nor should ANCA screening substitute for a careful history and physical examination. Biopsy of the upper airway or lungs may be required for diagnosis [8]. If renal involvement is detected by urinalysis, a kidney biopsy is also indicated, which will often show a pauci-immune necrotising glomerulonephritis. Effective treatment of sinus disease is crucial in WG, since recurrent sinusitis is implicated in ongoing disease. Recent reports describing successful treatment of complex cases of MPA and WG with rituximab suggests this may be a potential therapeutic option for relapsing ANCA-associated vasculitis in children [43,44]. Childhood PAN with systemic features is treated in a similar fashion in many centres. Although randomised controlled trials are urgently needed to determine the most effective induction and maintenance therapies in children, as well as reliable predictors of individual responses, reviews suggest an excellent overall prognosis with a 4-year mortality rate among children with PAN under 5% [5]. Takayasu arteritis As with all vasculitides, early diagnosis and aggressive therapy are important in Takayasu arteritis (TA) to prevent irreversible vessel damage with resulting compromise of vital organs. Available data

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suggest that clinical manifestations of TA in children are similar to those in adults [45]. Once TA is suspected, angiography has been the standard method used for diagnosis [46]. The size of the vessels involved and the spotty nature of the vascular inflammation make biopsy impractical and laboratory markers may be entirely normal despite ongoing inflammation, so imaging offers a potentially more sensitive test for residual disease [47]. In recent years, CT and especially MR angiograms (with IV gadolinium) have proven to be as useful as traditional angiograms and far less invasive [46]. MR has the added advantage of revealing evidence of ongoing vessel wall inflammation. Positron emission tomography may be of value; however, it remains expensive and of limited availability. In contrast to PAN and WG, the EULAR guidelines offer low levels of evidence for treatment of TA [26]. Early initiation of corticosteroids is indicated, and immunosuppressive medications are recommended as adjunctive therapy, although they have shown variable efficacy. Case studies and small series on the use of immunosuppressive medications and anti-TNF agents have been published in the paediatric literature; however, larger multicentre studies are clearly needed. There is no high level evidence for the monitoring of patients with TA; however, the recently published EULAR guidelines state that periodic MR imaging along with monitoring of inflammatory markers assists assessment of disease activity [26]. Primary angiitis of the central nervous system Primary angiitis of the central nervous system (PACNS) remains both a diagnostic and a therapeutic challenge [48]. By definition, systemic manifestations of disease are usually absent, acute-phase reactants are typically normal and examination of CSF might be unrevealing as well. Thus, to make the diagnosis before the patient develops severe injury, clinicians must have a high level of suspicion when children have even minimal suggestion of a vasculitis. Review of the clinical spectrum of disease in a large cohort of patients revealed that headache (80%) and focal neurologic deficits (78%) were the most common presenting complaints, followed by hemiparesis in 62% [48]. When a clearly defined infectious, toxic or vascular abnormality cannot account for such findings, brain and cerebral vessel imaging are indicated. Biopsy is also useful in excluding mimics of CNS vasculitis, especially atypical infections that could worsen on immunosuppressive therapy. PACNS may be rapidly progressive and neurologically devastating, so the risks of diagnostic procedures must be weighed against the need for prompt diagnosis and initiation of therapy. Randomised trials are absent, but treatment in the published reports invariably includes corticosteroids and a potent immunosuppressive agent, usually cyclophosphamide. Outcomes using these agents to achieve initial disease control, followed by methotrexate or azathioprine for maintenance therapy, have been excellent [48]. Churg–Strauss syndrome Churg–Strauss syndrome (CSS) is extremely rare in children [49]. The prodromal phase of CSS is commonly manifest only as allergic rhinitis and asthma, and it may persist for many years. The second phase is characterised by worsening asthma, peripheral eosinophilia and pulmonary infiltrates. Only during the third, or vasculitic phase, do manifestations of systemic vasculitis become evident, with weight loss, fever, arthralgia, myalgia, nodular rash and neuropathy reported. Interestingly, asthma symptoms usually subside during the vasculitic phase. In some cases, it may be difficult to differentiate CSS from PAN, although in CSS renal hypertension and nephritis are uncommon, and peripheral eosinophilia is quite striking. Tissue biopsy is generally diagnostic, with significant perivascular eosinophilic infiltrates and occasional extravascular granulomas. ANCA directed against both PR-3 and MPO may be seen. Some data in adult populations indicate that ANCA-positive patients have more significant systemic disease and organ involvement, while the ANCA-negative population may have more frequent cardiac disease [50]. The optimal regimen for treating CSS is not clear, although an initial aggressive remittive therapy, followed by a lower-level maintenance treatment, may offer the best combination of safety and efficacy [50]. Conclusion Although there have been substantial advances in the past 10 years, significant deficits remain in our knowledge regarding pathogenesis and optimal treatments for childhood vasculitis. Now that we

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can effect remission at high rates in most conditions, we need to reflect on the next 60 or more potential years of the child’s life we are managing. Availability of improved classification criteria for children should prompt planning for multicentre-controlled studies of treatment for these rare but important diseases.

Key points      

New classification criteria have been developed for HSP, TA, WG and childhood PAN Infections are important triggers for all childhood vasculitides Regarding the management of common pediatric vasculitic syndromes Corticosteroids are probably not indicated for the prevention of renal involvement in HSP Alternative treatment strategies are being studied in KD patients resistant to IVIG MR angiograms have emerged as safe alternatives for large vessel vasculitis (e.g., TA), however their value in small-mid size artery involvement is limited

Research agenda  Controlled multicentre studies for management and treatment of all childhood vasculitides.

References [1] Jennette JC, Falk RJ. Do vasculitis categorization systems really matter? Curr Rheumatol Rep 2000;2:430–8. *[2] Fries JF, Hunder GG, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum 1990;33:1135–6. *[3] Lie JT. Nomenclature and classification of vasculitis: plus ca change, plus c’est la meme chose. Arthritis Rheum 1994;37: 181–6. *[4] Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187–92. *[5] Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr 2004;145: 517–22. [6] Bakkaloglu A, Ozen S, Baskin E, et al. The significance of antineutrophil cytoplasmic antibody in microscopic polyangitis and classic polyarteritis nodosa. Arch Dis Child 2001;85:427–30. *[7] Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 2006;65:936–41. *[8] Ozen S., Pistorio A., Dolezalova, P., et al. (in press). The EULAR/PRINTO/PReS crıterıa for Wegener Granulomatosis. Ankara 2008. Ann Rheum Dis. [9] Ozen S., Pistorio A., Iusan M., et al. (in press). The EULAR/PRINTO/PReS crıterıa for Henoch- Schonlein purpura. Ankara 2008. Ann Rheum Dis. [10] Ozen, S., Pistorio, A., Iusan, M., et al. (in press). The EULAR/PRINTO/PReS crıterıa for chıldhood polyarterıtıs nodosa. Ankara 2008. Ann Rheum Dis. [11] Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 2007;66:222–7. [12] Jennette JC, Falk RJ. New insight into the pathogenesis of vasculitis associated with antineutrophil cytoplasmic autoantibodies. Curr Opin Rheumatol 2008;20:55–60. [13] Borgmann S, Haubitz M. Genetic impact of pathogenesis and prognosis of ANCA-associated vasculitides. Clin Exp Rheumatol 2004;22:S79–86. [14] Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110:955–63. [15] Dedeoglu F, Sundel RP. Vasculitis in children. Rheum Dis Clin North Am 2007;33:555–83. [16] Rowley AH, Baker SC, Orenstein JM, et al. Searching for the cause of Kawasaki disease–cytoplasmic inclusion bodies provide new insight. Nature Rev 2008;6:394–401. [17] Coppo R, Amore A, Gianoglio B. Clinical features of Henoch-Schonlein purpura. Italian group of renal immunopathology. Ann Med Interne 1999;150:143–50. [18] Burgner D, Davila S, Breunis WB, et al. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease. PLoS Genet 2009;5:e1000319.

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[19] Cheung YF, Huang GY, Chen SB, et al. Inflammatory gene polymorphisms and susceptibility to Kawasaki disease and its arterial sequelae. Pediatrics 2008;122:e608–614. [20] Yalcinkaya F, Ozcakar B, Kasapcopur A, et al. Prevalence of MEFV mutations in childhood PAN. J Pediatr 2007;151:675–8. [21] Pipitone N, Salvarani C. Role of imaging in vasculitis and connective tissue diseases. Best Pract Res 2008;22:1075–91. [22] Binstadt BA, Levine JC, Nigrovic PA, et al. Coronary artery dilation among patients presenting with systemic-onset juvenile idiopathic arthritis. Pediatrics 2005;116:e89–93. [23] Sabatier F, Camoin-Jau L, Anfosso F, et al. Circulating endothelial cells, microparticles and progenitors: key players towards the definition of vascular competence. J Cell Mol Med 2009;13:454–71. [24] Watts R, Harper L, Jayne D, et al. Translational research in autoimmunity: aims of therapy in vasculitis. Rheumatology (Oxford) 2005;44:573–6. *[25] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68:310–7. *[26] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68:318–23. *[27] Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol 2008;26:S94–104. [28] Huber AM, King J, McLaine P, et al. A randomized, placebo-controlled trial of prednisone in early Henoch Schonlein Purpura [ISRCTN85109383]. BMC Med 2004;2:7. [29] Ronkainen J, Koskimies O, Ala-Houhala M, et al. Early prednisone therapy in Henoch-Schonlein purpura: a randomized, double-blind, placebo-controlled trial. J Pediatr 2006;149:241–7. [30] Weiss PF, Feinstein JA, Luan X, et al. Effects of corticosteroid on Henoch-Schonlein purpura: a systematic review. Pediatrics 2007;120:1079–87. [31] Chartapisak W, Opastiraku S, Willis NS, et al. Prevention and treatment of renal disease in Henoch-Schonlein purpura: a systematic review. Arch Dis Child 2009;94:132–7. [32] Zaffanello M, Brugnara M, Franchini M. Therapy for children with henoch-schonlein purpura nephritis: a systematic review. ScientificWorldJournal 2007;7:20–30. [33] Shenoy M, Bradbury MG, Lewis MA, et al. Outcome of Henoch-Schonlein purpura nephritis treated with long-term immunosuppression. Pediatr Nephrol 2007;22:1717–22. [34] Zampetti A, Rigante D, Bersani G, et al. Longitudinal study of microvascular involvement by nailfold capillaroscopy in children with Henoch-Schonlein purpura. Clin Rheumatol 2009. [35] Falcini F. Kawasaki disease. Curr Opin Rheumatol 2006;18:33–8. [36] Hsieh KS, Weng KP, Lin CC, et al. Treatment of acute Kawasaki disease: aspirin’s role in the febrile stage revisited. Pediatrics 2004;114:e689–93. [37] Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007;356:663–75. [38] Okada K, Hara J, Maki I, et al. Pulse methylprednisolone with gammaglobulin as an initial treatment for acute Kawasaki disease. Eur J Pediatr 2009;168:181–5. [39] Furukawa T, Kishiro M, Akimoto K, et al. Effects of steroid pulse therapy on immunoglobulin-resistant Kawasaki disease. Arch Dis Child 2008;93:142–6. [40] Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005;146:662–7. [41] Nakamura Y, Aso E, Yashiro M, et al. Mortality among persons with a history of Kawasaki disease in Japan: can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae? Acta Paediatr 2005;94:429–34. [42] Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008;153:117–21. [43] Brunner J, Freund M, Prelog M, et al. Successful treatment of severe juvenile microscopic polyangiitis with rituximab. Clin Rheumatol 2009. [44] Patel AM, Lehman TJ. Rituximab for severe refractory pediatric Wegener granulomatosis. J Clin Rheumatol 2008;14: 278–80. [45] Ozen S, Bakkaloglu A, Dusunsel R, et al. Childhood vasculitides in Turkey: a nationwide survey. Clin Rheumatol 2007;26: 196–200. [46] Tann OR, Tulloh RM, Hamilton MC. Takayasu’s disease: a review. Cardiol Young 2008;18:250–9. [47] Pipitone N, Versari A, Salvarani C. Role of imaging studies in the diagnosis and follow-up of large-vessel vasculitis: an update. Rheumatology (Oxford) 2008;47:403–8. *[48] Benseler SM. Central nervous system vasculitis in children. Curr Rheumatol Rep 2006;8:442–9. [49] Boyer D, Vargas SO, Slattery D, et al. Churg-Strauss syndrome in children: a clinical and pathologic review. Pediatrics 2006;118:e914–20. [50] Grau RG. Churg-Strauss syndrome: 2005–2008 update. Curr Rheumatol Rep 2008;10:453–8.