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Vasculitis in children
SYMPOSIUM: CONNECTIVE TISSUE & BONE
Vasculitis in children
Classification of paediatric vasculitis
Alison Kelly
Predominantly large vessel vasculitis C Takayasu arteritis
E Jane Tizard
Predominantly medium sized vessel vasculitis C Kawasaki disease C Polyarteritis nodosa C Cutaneous polyarteritis
Abstract The term vasculitis refers to inflammation in the blood vessel walls. The vasculitic conditions which affect children are a varied group of diseases many of which carry a potentially significant morbidity and mortality. This review describes the classification, diagnosis and management of the main primary systemic paediatric vasculitides. The conditions described ¨nlein purpura, Kawasaki disease, Takayasu’s arterinclude Henoch-Scho itis, polyarteritis nodosa, and the ANCA associated vasculitic (AAV) conditions Wegener’s granulomatosis, microscopic polyangiitis and ChurgStrauss syndrome.
Predominantly small vessel vasculitis - Granulomatous C Wegener’s granulomatosis C Churg-Strauss syndrome Predominantly small vessel vasculitis - Non-granulomatous C Henoch-Scho ¨nlein purpura C Microscopic polyangiitis C Isolated cutaneous leucocytoclastic vasculitis C Hypocomplementaemic urticarial vasculitis Others C Behc ¸et’s disease C Vasculitis secondary to infection, malignancies, and drugs, including hypersensitivity vasculitis C Vasculitis associated with connective tissue diseases C Isolated vasculitis of the central nervous system C Cogan’s syndrome C Unclassified
Keywords AAV; ANCA; children; Churg-Strauss syndrome; Henoch¨nlein purpura; Kawasaki disease; microscopic polyangiitis; paediScho atric; polyarteritis nodosa; Takayasu arteritis; vasculitis; Wegener’s granulomatosis
Introduction The term vasculitis is used when there is inflammation within the blood vessel walls. The inflammatory infiltrate involved may have mainly neutrophils, eosinophils or mononuclear cells. Primary vasculitis is when the aetiology of the vasculitis is not secondary to a known infection, a specific disease such as systemic lupus erythematosus, or drugs. This article describes the main primary systemic vasculitides that affect children. The commonest two are Henoch-Scho¨nlein purpura and Kawasaki disease. Others, although very rare, are often associated with significant morbidity and mortality and require aggressive treatment. In addition their diagnosis may prove to be difficult and delayed relying on a combination of clinical criteria, imaging and pathology.
Adapted from Ozen et al., 2006.
Table 1
Rheumatology European Society (PReS) proposed a paediatric vasculitis classification which is currently being validated (See Table 1).
ANCA associated vasculitis Anti-neutrophil cytoplasmic antibodies (ANCA) were first described in patients with segmental necrotizing glomerulonephritis in 1982. ANCA were subsequently demonstrated in adults with the vasculitic conditions Wegener’s granulomatosis and microscopic polyarteritis. There is a group of childhood vasculitides which is classified as ANCA associated vasculitis (AAV) because in these conditions the ANCA result is often positive. AAV in children includes Wegener’s granulomatosis, and microscopic polyangiitis and Churg-Strauss syndrome. The incidence of AAV in children is 0.24 per 100,000 with Wegener’s granulomatosis being the commonest. There are two main types of ANCA which refer to the differing patterns of immunofluorescent staining (see Figure 1). These two types are perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA). The pANCA is typically directed against myeloperoxidase (MPO-ANCA), and cANCA is directed against proteinase 3 antigen (PR3-ANCA). ANCA may be useful both in the diagnosis and the follow up of children with these vasculitides. A recent retrospective review of children with Wegener’s granulomatosis reported that 95.5% of cases had a positive ANCA (80% with the cANCA pattern PR3-ANCA).
Classification of childhood vasculitis Vessel size Vessel size is usually used to classify vasculitis. Previously paediatric vasculitis used adult vasculitis classification systems. These have limitations however when applied to the paediatric population because there are some vasculitides specific to adults, for example temporal arteritis and some which are predominantly childhood conditions for example Kawasaki disease. A consensus group in 2006 of the European League Against Rheumatism (EULAR) and the Paediatric
Alison Kelly MBBS MRCPCH is a Specialist Registrar Paediatrics at the Royal United Hospital Bath, Bath, UK. E Jane Tizard FRCP FRCPCH is a Consultant Paediatric Nephrologist at the Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK.
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Anti-neutrophil cytoplasmic antibodies (ANCA) immunoflourescent staining patterns. a cANCA e diffuse cytoplasmic staining. b pANCA e perinuclear staining. Figure 1
¨nlein purpura Henoch-Scho
Pathology: The exact cause of HSP is unknown. The immunopathology involves IgA deposition. The skin has a leucocytoclastic vasculitis with infiltration of polymorphonuclear cells and mononuclear cells. IgA is found in both the purpuric skin lesions and the non affected areas. The renal pathology is the same as IgA nephropathy with a focal and segmental proliferative glomerulonephritis. This may progress with formation of crescentic lesions.
Henoch-Scho¨nlein Purpura (HSP) is the commonest vasculitis of childhood. It was probably first described in 1801 by Heberden. Scho¨nlein then described a case in 1837 and thirty years later Henoch noted gastrointestinal and renal involvement. HSP is a small vessel IgA immune complex mediated small vessel leukocytoclastic vasculitis. The incidence of HSP is 10e20.4 per 100 000 children. Over 75% of cases are under 10 years of age. One study showed an incidence of 70.3/100 000 in those between 4e7 years. Most children with HSP will make a full recovery. The mortality is <1% and the morbidity is usually due to renal involvement. The EULAR/PReS consensus group have endorsed classification criteria for HSP (see Table 2). Palpable purpura are mandatory plus at least one of the following four features: diffuse abdominal pain, acute arthritis/arthralgia, renal involvement (haematuria and/or proteinuria), or any biopsy showing predominant IgA deposition. There are no specific serological markers but investigations are used to evaluate the extent of any renal involvement or other organ involvement and if the diagnosis is uncertain autoimmune and streptococcal investigations should be considered.
Clinical features: The purpuric skin lesions, commonly over the lower limbs, usually spare the trunk and in the early stages can be urticarial or maculopapular (see Figure 2). In approximately 2% of cases bullous skin lesions form. The commonest abdominal symptom is colicky pain. Vomiting, diarrhoea and gastrointestinal haemorrhage can also occur but only about 2% will develop a large bleed. Steroids are often used for the symptomatic treatment of the abdominal pain however it usually resolves without treatment. One prospective study of prednisolone 1 mg/kg (max 50 mg) daily for two weeks followed by a weaning dose for two weeks showed a reduction in
¨nlein purpura Classification criteria for Henoch-Scho Palpable purpura (mandatory) in the presence of at least one of the following four features: C Diffuse abdominal pain C Arthritis (acute, any joint) or arthralgia C Renal involvement (any haematuria and/or proteinuria) C Any biopsy showing predominant IgA deposition Adapted from Ozen et al., 2006.
Table 2
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Figure 2 Typical HSP skin rash of the lower limb.
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the intensity of the abdominal pain and a reduction in the duration of the pain by a mean of 1.2 days. HSP arthritis is an acute self resolving arthritis which usually affects the large joints of the lower limbs. HSP less commonly causes other symptoms such as headache, mood changes, intracranial bleeds or infarction, carditis, alveolar haemorrhage, intussusception and pancreatitis. Investigations are used to evaluate the extent of any renal or other organ involvement and to exclude other conditions such as streptococcal infections or autoimmune diseases if the clinical diagnosis of HSP is uncertain.
order to try and reduce these renal complications the use of steroids early in the course of the disease has been investigated. A Cochrane review, however, found no benefit of steroids in the prevention of renal disease. This review included the largest randomised controlled study of prednisolone v placebo in HSP to date which found no benefit of steroids in preventing or ameliorating renal disease at one year from onset of disease. As severe disease is relatively uncommon there are few randomised controlled studies of treatment in this situation. There is therefore little evidence based treatment for these patients however some low grade evidence exists for the benefit of using immunosuppressive therapy in children with severe disease. In view of the possible long term sequelae timely referral to a paediatric nephrologist is recommended for those children with significant nephropathy at presentation so that treatment can be considered. See Figure 3. Patients who have experienced HSP nephritis are at risk of developing hypertension and in some cases chronic renal impairment and females should be monitored carefully for hypertension and proteinuria during pregnancy. Patients with a history of HSP nephritis should have life long follow up. The relative risk of long term renal impairment in patients presenting with nephrotic/nephritic syndrome is 12 times that of those with haematuria þ/ proteinuria alone.
Renal disease: Renal involvement in HSP can present as haematuria, proteinuria, nephrotic syndrome, renal impairment and hypertension. Renal disease has been quoted to affect between 20e60% of patients with HSP. It is usually evident within 4 weeks of the onset of the illness and 97% of renal involvement occurs within six months of onset of HSP. The incidence of severe renal disease is 5e7%, which includes acute nephritis, nephrotic syndrome or renal impairment. HSP nephritis is responsible for 1.5e3% of children with chronic kidney disease stage 5. It is the presence of acute severe renal disease that is predominantly responsible for any long term problems following HSP. In
Figure 3 Detection and referral of patients with HSP nephritis (Adapted from local guidelines developed by Dal Hothi and Bristol Paediatric Nephrologists).
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Kawasaki disease
Diagnostic criteria of KD
Tomisaku Kawasaki first described Kawasaki disease in Japan in 1967. It is a self limiting acute vasculitis affecting small and medium sized arteries. There is an infiltrate of neutrophils, macrophages and plasma cells and fibrinoid necrosis. Kawasaki disease predominantly affects young children with 80% of cases occurring in children less than 5 years of age, and has a peak incidence between 9 and 11 months. In England the incidence was reported in 2000 to be 8.1/100,000 children under the age of 5 years, whereas in Japan it is much higher up to 134.2/100,000. Kawasaki disease is an important vasculitis as it is the leading cause of acquired heart disease in childhood in the UK and if untreated up to 25% of cases will develop coronary artery aneurysms.
The diagnostic criteria of KD are: The presence of fever for five days or more duration plus four of the following principal features; 1) non purulent bilateral conjunctival injection 2) polymorphous rash (see Figure 4) 3) changes in the lips and oral cavity e possible features are erythema, cracked lips, strawberry tongue, oropharyngeal mucosal injection 4) cervical lymphadenopathy >1.5 cm diameter 5) changes in the extremities or perineal area e possible features are erythema of the palms and soles, swelling of the hands and feet, and later periungual peeling of fingers or toes. Other diseases with similar clinical findings should be excluded. If coronary artery aneurysms are detected in the presence of a fever then fewer than four of the principal features are needed.
Diagnosis of KD: The diagnosis is based on clinical criteria which include the presence of fever for five days plus four of the following five features: changes in peripheral extremities or perineal area, polymorphous exanthema (see Figure 4), bilateral conjunctival injection, changes in the lips and oral cavity, cervical lymphadenopathy (see Table 3). Fewer than four are needed for the diagnosis in the presence of coronary artery aneurysms. Care should also be taken not to miss the diagnosis in cases with fewer than four of the features, particularly in very young patients who more commonly exhibit fewer of the features, sometimes termed ‘‘incomplete’’ or ‘‘atypical’’ KD. It is also important to remember that the features may not all appear simultaneously and a careful history is required to identify them. Other recognised KD findings include extreme irritability, arthritis, diarrhoea and vomiting, hepatomegaly, carditis, erythema and induration at the BCG site, and uveitis. Very rarely there may be palpable dilatations of the femoral, axillary or brachial arteries, which may lead to ischemic symptoms.
Table 3
later in the illness. Intrahepatic congestion can result in raised liver transaminases and bilirubin. An echocardiogram is performed routinely in all suspected cases but a normal echocardiogram at presentation does not exclude the diagnosis, with most cardiac abnormalities occurring within 6e8 weeks of diagnosis. Treatment: KD is treated with intravenous immunoglobulin and high dose aspirin in the acute phase of the illness followed by low dose aspirin longer term. If there is failure of response to the immunoglobulin, which is evident by recurrent pyrexia, then the immunoglobulin may be repeated. Immunoglobulin has been shown to significantly reduce the incidence of coronary artery aneurysms when given within the first 10 days of the illness. If coronary artery changes occur they may result in coronary artery thrombosis and myocardial infarction. It has been suggested that KD patients including even those without coronary artery changes may be at risk of increased atherosclerosis and hypertension in adulthood and should be monitored long-term for these affects.
Investigations: Investigations are performed to exclude other diagnoses, such as infections, and to examine the extent of the illness. The C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated and there is often an anaemia and leucocytosis. A thrombocytopenia may be present in the first week of the illness in addition to the more typical thrombocytosis
Systemic polyarteritis nodosa Systemic polyarteritis nodosa (PAN) was described in 1866 by Kussmaul and Maier. It is a systemic necrotizing vasculitis of medium and small arteries with aneurysm formation. There is cellular infiltration and fibrinoid necrosis of the media. PAN is a multi-system disease. There is a cutaneous form, known as benign cutaneous polyarteritis nodosa (BCPAN) or cutaneous polyarteritis, which has a much better prognosis. Cutaneous polyarteritis may affect the skin, muscles, joints and peripheral nerves and may represent one spectrum of the same disease. Cutaneous PAN requires clinical vigilance for any systemic organ involvement. Systemic PAN is rare in children. A recent multicentre study of all types of paediatric polyarteritis found 110 patients followed in the past five years at 21 different paediatric centres from Europe, Turkey, United States and Brazil.
Figure 4 Skin rash in Kawasaki disease.
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Takayasu arteritis
Diagnosis of PAN: A EULAR/PReS consensus group proposed that diagnosis of PAN requires a biopsy showing a small and medium sized artery necrotising vasculitis or angiographic abnormalities (aneurysms or occlusions) in addition to at least two of the systemic features shown below: Skin involvement (livedo reticularis, tender subcutaneous nodules, other vasculitic lesions) Myalgia or muscle tenderness Systemic hypertension Mononeuropathy or polyneuropathy Abnormal urine analysis and/or impaired renal function (GFR < 50%) Testicular pain or tenderness Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or central nervous system).
Takayasu arteritis (TA) was first described as the ‘‘pulseless disease’’ in 1948. Forty years earlier Takayasu, a Japanese ophthalmologist, described the retinal vessel changes of this disease. TA is a large vessel pan arteritis predominantly affecting the aorta and its main branches. It is a rare condition in children. Unlike HSP and Kawasaki disease it is not a self-limiting disease. It is usually a chronic disease with relapses even whilst on treatment. TA is commonest in females in the third decade. The aetiology of TA is unknown. Symptoms in children include headache, abdominal pain, myalgia, arthralgia, fever, weight loss, limb claudication, cerebrovascular events, angina, and visual disturbance. Clinical examination may reveal hypertension, aortic bruits, reduced or absent peripheral pulses, and blood pressure differences. Investigations reveal a raised ESR, and in some cases a leucocytosis and anaemia. ANCA is usually negative. Chest radiographs may show a wide mediastinum, cardiomegally or an abnormal aortic outline. Arteriography and CT or Magnetic Resonance angiography provide the important imaging required for diagnosis and to monitor disease progression (see Figure 5). Aggressive treatment is indicated to minimise permanent vessel damage. High dose steroids are used to bring the disease into remission. One reported treatment regime in children includes steroids and cyclophosphamide to induce remission followed by methotrexate as maintenance with a tapered steroid dose. Usual maintenance therapy in TA uses combinations of steroid and azathioprine or methotrexate. Antihypertensive medication may be required and surgery may be required to alleviate severe ischaemia.
Aetiology: The aetiology of PAN is unknown. In adults there is an association with previous hepatitis B infection but this is less common in children. Clinical features: There is usually a gradual onset of constitutional symptoms including recurrent pyrexias, weight loss and myalgia. The other symptoms depend on the organs involved, which commonly are the skin, joints, gastrointestinal system and kidney. The cutaneous features possible include painful subcutaneous nodules especially of the feet, palpable purpura, livedo reticularis, necrotic and gangrenous lesions, panniculitis and oedema. Abdominal pain is common which is thought to represent visceral ischemia, and testicular pain is a feature in boys. Arthralgia and arthritis commonly occurs. Renal involvement can manifest as hypertension, proteinuria and haematuria and less commonly for PAN a rapidly progressive nephritis. Neurological involvement commonly presents as a peripheral neuropathy and less commonly as central nervous system features, for example seizures. Cardio-respiratory features are uncommon. The mortality figures for this rare condition vary; the mortality of PAN in children at Great Ormond Street Hospital was quoted as approximately 10%. Investigation and treatment: Laboratory investigations reveal raised acute phase reactants and a leucocytosis. Other findings may include thrombocytosis, anaemia, proteinuria, and haematuria. A positive ANCA is sometimes seen in PAN but its presence usually raises the suspicion of the different diagnosis of microscopic polyangiitis (see below). A recent multicentre survey found 6 out of 47 children with PAN had a positive ANCA. Biopsies and angiograms are used to find evidence of the characteristic vascular changes such as aneurysms. In treating PAN the usual practice is to induce remission with a regime of high dose steroid and cyclophosphamide. This is then followed with maintenance of remission using low dose steroid and azathioprine. Although this is the widely accepted approach it has not tested in a controlled trial. Plasma exchange has been used in severe life threatening cases however conclusions on its effectiveness remain unknown without larger studies. A retrospective review of 5 PAN cases treated with plasma exchange concluded that there was a good response in 4 of the cases.
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Figure 5 Thoracic imaging in Takayasu arteritis showing a very dilated aortic root (arrow).
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ANCA associated vasculitis Wegener’s granulomatosis Wegener’s granulomatosis (WG) is a necrotising granulomatous vasculitis of small blood vessels. The inflammatory infiltrate has polymorphonuclear leucocytes and mononuclear cells. The classical features are respiratory tract granulomas, a widespread small vessel vasculitis and a necrotising glomerulonephritis. Friedrich Wegener described the condition first in 1936. The cause is unknown. The ANCA investigation is usually positive and characteristically it is cANCA. Indeed the ANCA are even suggested to play a role in the aetiology because they have been shown to stimulate inflammation. EULAR/PReS recently published consensus criteria for the classification of WG in children to take into account the paediatric WG findings and investigations. These classification criteria are currently being validated and are as follows: Three of the following six features: Abnormal urinalysis (haematuria and/or significant proteinuria) Granulomatous inflammation on biopsy (if a kidney biopsy is done it characteristically shows necrotising pauci-immune glomerulonephritis). Nasal sinus inflammation Subglottic, tracheal, or endobronchial stenosis Abnormal chest x ray or CT PR3 ANCA or cANCA staining Clinical features: Children usually present with symptoms of the ears, nose and sinuses and constitutional symptoms of fever, lethargy and weight loss. Inflammatory changes of the upper respiratory tract may result in epistaxis, sinusitis, cough, and nasal septum perforation. Chondritis of the bridge of the nose leads to a classic saddle nose deformity. Granulomas may be visible on inspection of the nasal mucosa, oral ulcers may occur, and the possible ear pathology includes otitis media and deafness. Lesions of the tracheobronchial airways cause subglottic stenosis and stridor (see Figure 6). Biopsies of these lesions at laryngobronchoscopy can help to diagnose WG. Involvement of the lower respiratory tract may be asymptomatic and detected on imaging or may result in symptoms of cough, respiratory distress or haemoptysis.
Figure 7 Vasculitic skin lesions in Wegener’s granulomatosis.
Skin involvement may result in erythema, purpuric lesions, urticaria, ulcerative or necrotic lesions (see Figure 7). Skin involvement affects up to 50% during the course of the disease. In two series glomerulonephritis was reported in 61% and 88% of cases during the course of the illness. Orbital granulomatous pseudotumours can result in proptosis and these orbital lesions may be biopsied to confirm the diagnosis. Ocular inflammation has also been described including episcleritis/scleritis, conjunctivitis, uveitis, retinal vasculitis and optic neuritis. The other possible symptoms include a transient arthritis which typically resolves with control of the WG without long term joint damage. Cardiac involvement is rare but may include pericarditis, pancarditis, coronary arteritis and valvulitis. Venous thromboembolism may occur. Cranial nerve palsies, peripheral neuropathy, and cerebral infarction may also occur. Gastrointestinal disease can cause bowel perforation and involvement of the anus and rectum. Treatment: WG can be a devastating vasculitis, which typically flares with the reduction of immunosuppression. The mortality has been reported as high as 12% (39). Patients are usually treated with high dose steroids and cyclophosphamide to induce remission followed by lower dose steroids and azathioprine to maintain remission. There is a considerable risk of infection with
Figure 6 Bronchoscopy demonstrating narrowing of the left main bronchus in Wegener’s granulomatosis.
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cyclophosphamide and paediatric patients are currently being enrolled in a EUVAS (European Vasculitis Study Group) clinical trial of mycophenolate mofetil versus cyclophosphamide to induce remission in WG.
mofetil, rituximab, anti-TNF-a and anakinra and with international trials progress will be made. Meanwhile, at the clinical presentation level, it is the varied and possible constitutional nature of the clinical features which highlight the need to consider a diagnosis of vasculitis in any child with unexplained raised inflammatory markers and to perform appropriate investigations often in a specialist centre.
Microscopic polyangiitis Microscopic polyangiitis (MPA) is a small vessel necrotising nongranulomatous vasculitis. It is pauci-immune, showing few or no immune deposits. MPA affects arterioles, venules and capillaries. Microscopic polyangiitis was previously known as microscopic polyarteritis. The pathology is similar to WG but without granulomas. The main feature is the renal disease and this condition may encompass cases of what was previously known as idiopathic crescentic glomerulonephritis. Clinically there is a focal segmental necrotising glomerulonephritis and often a pulmonary capillaritis. It is commonly associated with p-ANCA positivity or less commonly c-ANCA positivity. One study found that 9 of 10 cases of paediatric MPA were ANCA positive (5 positive for MPOANCA, 4 positive for PR3-ANCA). These ANCA results in MPA demonstrated a very strong staining pattern. In contrast in the same study only 6 of 16 PAN cases showed ANCA positivity and these had mild staining patterns. The treatment of MPA is similar to that of Wegener’s granulomatosis with cyclophosphamide, steroids, azathioprine and plasma exchange for very severe cases.
Conflict of interest of authors None.
FURTHER READING Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, Silverman ED. Clinical features and outcome of pediatric Wegener’s granuolomatosis. Arthritis Rheum 2007; 57: 837e44. Bakkaloglu A, Ozen S, Baskin E, et al. The significance of antineutrophil antibody in microscopic polyangitis and classic polyarteritis nodosa. Arch Dis Child 2001; 85: 427e30. Brogan PA, Bose A, Burgner D, et al. Kawasaki disease:an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child 2002; 86: 286e90. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of pediatric rheumatology. 5th Edn. Elsevier Saunders, 2005. Chartapisak W, Opastiraku S, Willis NS, Craig JC, Hodson EM. Prevention ¨nlein purpura: and treatment of renal disease in Henoch-Scho a systematic review. Arch Dis Child 2009; 94(2): 132e7. Dillon MJ. Vasculitis treatment e new therapeutic approaches. Eur J Pediatr 2006; 165: 351e7. Eleftheriou D, Brogan PA. Vasculitis in children. Best Pract Res Clin Rheumatol 2009; 23: 309e23. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics 2007; 120: e1434e40. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic fever, Endocarditis, and Kawasaki disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004; 114: 1708e33. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicentre survey of 110 children. J Pediatr 2004; 145: 517e22. Ozen S, Duzova A, Bakkaloglu A, et al. Takayasu arteritis in children: preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate. J Pediatr 2007; 150: 72e6. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PreS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 2006; 65: 936e41. Tizard EJ, Dillon MJ. Wegener’s granulomatosis, polyarteritis nodosa, Behc¸et’s disease and relapsing polychondritis. Textbook of pediatric dermatology, vol. 2. 2nd Edn. Blackwell publishing, 2006. ¨nlein purpura. Arch Dis Child Tizard EJ, Hamilton-Ayres MJJ. Henoch-Scho Educ Pract Ed 2008; 93: 1e8. Zwerina J, Eger G, Englbrecht M, Manger B, Schett G. Churg-Strauss syndrome in childhood:a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 2008 [Epub article in press].
Churg-Strauss syndrome Churg and Strauss described this condition in 1951. It is extremely rare but does occur in children. It is a necrotising granulomatous vasculitis of small arteries and veins with an eosinophillic infiltrate. The aetiology is unknown. Children affected are usually already known to have asthma or allergic rhinitis and then develop worsening symptoms with pyrexias, eosinophilia, and pulmonary infiltrates. Clinical manifestations may include hypertension, pneumonitis, skin nodules, purpura, livedo reticularis, cardiac failure, nephritis and neuropathy. Churg Strauss syndrome is classified as an ANCA associated vasculitis however a recent study reported only 25% of childhood cases were positive. The treatment of CSS includes steroids, cyclophosphamide and plasma exchange.
Summary This review highlights that there are many unanswered questions in the field of paediatric vasculitis. With regards to HSP continued research is required to identify firstly ways to reduce the number of cases developing renal disease and secondly how to treat HSP renal disease. In Kawasaki disease methods to recognise the condition early are paramount with treatment having been proven to reduce the cardiovascular morbidity. Many of the knowledge limitations of the other vasculitides described are a result of the very small patient numbers. Polyarteritis nodosa, Takayasu arteritis and the ANCA associated vasculitides all have a significant morbidity and mortality which also limits the scope for trying new treatment methods, even if the current routine approaches have not themselves been through controlled trials. Hopefully with the development of newer immunosuppressant agents such as mycophenolate
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Practice points C
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Vasculitis in children may present with a wide range of clinical features including skin rash, fever, malaise, weight loss, abdominal pain, hypertension, proteinuria, arthritis, myalgia, and features of any of the major organ systems. ANCA may be useful in the diagnosis and follow up of children with Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. If children with HSP have significant renal involvement discuss with a paediatric nephrologist for consideration of renal biopsy and possible immunosuppression.
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Children who have had HSP nephritis should have life long follow up. Treat Kawasaki disease with immunoglobulin without delay to reduce the incidence of coronary artery aneurysms. Consider a diagnosis of Kawasaki disease even if fewer than the required features are present particularly in very young patients, and in cases when the features do not all occur simultaneously. Consider a diagnosis of one of the rarer childhood vasculitides in children with persistent unexplained raised inflammatory markers and refer for investigation often to a specialist centre.
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Vasculitis in children
Classification of paediatric vasculitis
Alison Kelly
Predominantly large vessel vasculitis C Takayasu arteritis
E Jane Tizard
Predominantly medium sized vessel vasculitis C Kawasaki disease C Polyarteritis nodosa C Cutaneous polyarteritis
Abstract The term vasculitis refers to inflammation in the blood vessel walls. The vasculitic conditions which affect children are a varied group of diseases many of which carry a potentially significant morbidity and mortality. This review describes the classification, diagnosis and management of the main primary systemic paediatric vasculitides. The conditions described ¨nlein purpura, Kawasaki disease, Takayasu’s arterinclude Henoch-Scho itis, polyarteritis nodosa, and the ANCA associated vasculitic (AAV) conditions Wegener’s granulomatosis, microscopic polyangiitis and ChurgStrauss syndrome.
Predominantly small vessel vasculitis - Granulomatous C Wegener’s granulomatosis C Churg-Strauss syndrome Predominantly small vessel vasculitis - Non-granulomatous C Henoch-Scho ¨nlein purpura C Microscopic polyangiitis C Isolated cutaneous leucocytoclastic vasculitis C Hypocomplementaemic urticarial vasculitis Others C Behc ¸et’s disease C Vasculitis secondary to infection, malignancies, and drugs, including hypersensitivity vasculitis C Vasculitis associated with connective tissue diseases C Isolated vasculitis of the central nervous system C Cogan’s syndrome C Unclassified
Keywords AAV; ANCA; children; Churg-Strauss syndrome; Henoch¨nlein purpura; Kawasaki disease; microscopic polyangiitis; paediScho atric; polyarteritis nodosa; Takayasu arteritis; vasculitis; Wegener’s granulomatosis
Introduction The term vasculitis is used when there is inflammation within the blood vessel walls. The inflammatory infiltrate involved may have mainly neutrophils, eosinophils or mononuclear cells. Primary vasculitis is when the aetiology of the vasculitis is not secondary to a known infection, a specific disease such as systemic lupus erythematosus, or drugs. This article describes the main primary systemic vasculitides that affect children. The commonest two are Henoch-Scho¨nlein purpura and Kawasaki disease. Others, although very rare, are often associated with significant morbidity and mortality and require aggressive treatment. In addition their diagnosis may prove to be difficult and delayed relying on a combination of clinical criteria, imaging and pathology.
Adapted from Ozen et al., 2006.
Table 1
Rheumatology European Society (PReS) proposed a paediatric vasculitis classification which is currently being validated (See Table 1).
ANCA associated vasculitis Anti-neutrophil cytoplasmic antibodies (ANCA) were first described in patients with segmental necrotizing glomerulonephritis in 1982. ANCA were subsequently demonstrated in adults with the vasculitic conditions Wegener’s granulomatosis and microscopic polyarteritis. There is a group of childhood vasculitides which is classified as ANCA associated vasculitis (AAV) because in these conditions the ANCA result is often positive. AAV in children includes Wegener’s granulomatosis, and microscopic polyangiitis and Churg-Strauss syndrome. The incidence of AAV in children is 0.24 per 100,000 with Wegener’s granulomatosis being the commonest. There are two main types of ANCA which refer to the differing patterns of immunofluorescent staining (see Figure 1). These two types are perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA). The pANCA is typically directed against myeloperoxidase (MPO-ANCA), and cANCA is directed against proteinase 3 antigen (PR3-ANCA). ANCA may be useful both in the diagnosis and the follow up of children with these vasculitides. A recent retrospective review of children with Wegener’s granulomatosis reported that 95.5% of cases had a positive ANCA (80% with the cANCA pattern PR3-ANCA).
Classification of childhood vasculitis Vessel size Vessel size is usually used to classify vasculitis. Previously paediatric vasculitis used adult vasculitis classification systems. These have limitations however when applied to the paediatric population because there are some vasculitides specific to adults, for example temporal arteritis and some which are predominantly childhood conditions for example Kawasaki disease. A consensus group in 2006 of the European League Against Rheumatism (EULAR) and the Paediatric
Alison Kelly MBBS MRCPCH is a Specialist Registrar Paediatrics at the Royal United Hospital Bath, Bath, UK. E Jane Tizard FRCP FRCPCH is a Consultant Paediatric Nephrologist at the Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK.
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Anti-neutrophil cytoplasmic antibodies (ANCA) immunoflourescent staining patterns. a cANCA e diffuse cytoplasmic staining. b pANCA e perinuclear staining. Figure 1
¨nlein purpura Henoch-Scho
Pathology: The exact cause of HSP is unknown. The immunopathology involves IgA deposition. The skin has a leucocytoclastic vasculitis with infiltration of polymorphonuclear cells and mononuclear cells. IgA is found in both the purpuric skin lesions and the non affected areas. The renal pathology is the same as IgA nephropathy with a focal and segmental proliferative glomerulonephritis. This may progress with formation of crescentic lesions.
Henoch-Scho¨nlein Purpura (HSP) is the commonest vasculitis of childhood. It was probably first described in 1801 by Heberden. Scho¨nlein then described a case in 1837 and thirty years later Henoch noted gastrointestinal and renal involvement. HSP is a small vessel IgA immune complex mediated small vessel leukocytoclastic vasculitis. The incidence of HSP is 10e20.4 per 100 000 children. Over 75% of cases are under 10 years of age. One study showed an incidence of 70.3/100 000 in those between 4e7 years. Most children with HSP will make a full recovery. The mortality is <1% and the morbidity is usually due to renal involvement. The EULAR/PReS consensus group have endorsed classification criteria for HSP (see Table 2). Palpable purpura are mandatory plus at least one of the following four features: diffuse abdominal pain, acute arthritis/arthralgia, renal involvement (haematuria and/or proteinuria), or any biopsy showing predominant IgA deposition. There are no specific serological markers but investigations are used to evaluate the extent of any renal involvement or other organ involvement and if the diagnosis is uncertain autoimmune and streptococcal investigations should be considered.
Clinical features: The purpuric skin lesions, commonly over the lower limbs, usually spare the trunk and in the early stages can be urticarial or maculopapular (see Figure 2). In approximately 2% of cases bullous skin lesions form. The commonest abdominal symptom is colicky pain. Vomiting, diarrhoea and gastrointestinal haemorrhage can also occur but only about 2% will develop a large bleed. Steroids are often used for the symptomatic treatment of the abdominal pain however it usually resolves without treatment. One prospective study of prednisolone 1 mg/kg (max 50 mg) daily for two weeks followed by a weaning dose for two weeks showed a reduction in
¨nlein purpura Classification criteria for Henoch-Scho Palpable purpura (mandatory) in the presence of at least one of the following four features: C Diffuse abdominal pain C Arthritis (acute, any joint) or arthralgia C Renal involvement (any haematuria and/or proteinuria) C Any biopsy showing predominant IgA deposition Adapted from Ozen et al., 2006.
Table 2
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Figure 2 Typical HSP skin rash of the lower limb.
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the intensity of the abdominal pain and a reduction in the duration of the pain by a mean of 1.2 days. HSP arthritis is an acute self resolving arthritis which usually affects the large joints of the lower limbs. HSP less commonly causes other symptoms such as headache, mood changes, intracranial bleeds or infarction, carditis, alveolar haemorrhage, intussusception and pancreatitis. Investigations are used to evaluate the extent of any renal or other organ involvement and to exclude other conditions such as streptococcal infections or autoimmune diseases if the clinical diagnosis of HSP is uncertain.
order to try and reduce these renal complications the use of steroids early in the course of the disease has been investigated. A Cochrane review, however, found no benefit of steroids in the prevention of renal disease. This review included the largest randomised controlled study of prednisolone v placebo in HSP to date which found no benefit of steroids in preventing or ameliorating renal disease at one year from onset of disease. As severe disease is relatively uncommon there are few randomised controlled studies of treatment in this situation. There is therefore little evidence based treatment for these patients however some low grade evidence exists for the benefit of using immunosuppressive therapy in children with severe disease. In view of the possible long term sequelae timely referral to a paediatric nephrologist is recommended for those children with significant nephropathy at presentation so that treatment can be considered. See Figure 3. Patients who have experienced HSP nephritis are at risk of developing hypertension and in some cases chronic renal impairment and females should be monitored carefully for hypertension and proteinuria during pregnancy. Patients with a history of HSP nephritis should have life long follow up. The relative risk of long term renal impairment in patients presenting with nephrotic/nephritic syndrome is 12 times that of those with haematuria þ/ proteinuria alone.
Renal disease: Renal involvement in HSP can present as haematuria, proteinuria, nephrotic syndrome, renal impairment and hypertension. Renal disease has been quoted to affect between 20e60% of patients with HSP. It is usually evident within 4 weeks of the onset of the illness and 97% of renal involvement occurs within six months of onset of HSP. The incidence of severe renal disease is 5e7%, which includes acute nephritis, nephrotic syndrome or renal impairment. HSP nephritis is responsible for 1.5e3% of children with chronic kidney disease stage 5. It is the presence of acute severe renal disease that is predominantly responsible for any long term problems following HSP. In
Figure 3 Detection and referral of patients with HSP nephritis (Adapted from local guidelines developed by Dal Hothi and Bristol Paediatric Nephrologists).
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Kawasaki disease
Diagnostic criteria of KD
Tomisaku Kawasaki first described Kawasaki disease in Japan in 1967. It is a self limiting acute vasculitis affecting small and medium sized arteries. There is an infiltrate of neutrophils, macrophages and plasma cells and fibrinoid necrosis. Kawasaki disease predominantly affects young children with 80% of cases occurring in children less than 5 years of age, and has a peak incidence between 9 and 11 months. In England the incidence was reported in 2000 to be 8.1/100,000 children under the age of 5 years, whereas in Japan it is much higher up to 134.2/100,000. Kawasaki disease is an important vasculitis as it is the leading cause of acquired heart disease in childhood in the UK and if untreated up to 25% of cases will develop coronary artery aneurysms.
The diagnostic criteria of KD are: The presence of fever for five days or more duration plus four of the following principal features; 1) non purulent bilateral conjunctival injection 2) polymorphous rash (see Figure 4) 3) changes in the lips and oral cavity e possible features are erythema, cracked lips, strawberry tongue, oropharyngeal mucosal injection 4) cervical lymphadenopathy >1.5 cm diameter 5) changes in the extremities or perineal area e possible features are erythema of the palms and soles, swelling of the hands and feet, and later periungual peeling of fingers or toes. Other diseases with similar clinical findings should be excluded. If coronary artery aneurysms are detected in the presence of a fever then fewer than four of the principal features are needed.
Diagnosis of KD: The diagnosis is based on clinical criteria which include the presence of fever for five days plus four of the following five features: changes in peripheral extremities or perineal area, polymorphous exanthema (see Figure 4), bilateral conjunctival injection, changes in the lips and oral cavity, cervical lymphadenopathy (see Table 3). Fewer than four are needed for the diagnosis in the presence of coronary artery aneurysms. Care should also be taken not to miss the diagnosis in cases with fewer than four of the features, particularly in very young patients who more commonly exhibit fewer of the features, sometimes termed ‘‘incomplete’’ or ‘‘atypical’’ KD. It is also important to remember that the features may not all appear simultaneously and a careful history is required to identify them. Other recognised KD findings include extreme irritability, arthritis, diarrhoea and vomiting, hepatomegaly, carditis, erythema and induration at the BCG site, and uveitis. Very rarely there may be palpable dilatations of the femoral, axillary or brachial arteries, which may lead to ischemic symptoms.
Table 3
later in the illness. Intrahepatic congestion can result in raised liver transaminases and bilirubin. An echocardiogram is performed routinely in all suspected cases but a normal echocardiogram at presentation does not exclude the diagnosis, with most cardiac abnormalities occurring within 6e8 weeks of diagnosis. Treatment: KD is treated with intravenous immunoglobulin and high dose aspirin in the acute phase of the illness followed by low dose aspirin longer term. If there is failure of response to the immunoglobulin, which is evident by recurrent pyrexia, then the immunoglobulin may be repeated. Immunoglobulin has been shown to significantly reduce the incidence of coronary artery aneurysms when given within the first 10 days of the illness. If coronary artery changes occur they may result in coronary artery thrombosis and myocardial infarction. It has been suggested that KD patients including even those without coronary artery changes may be at risk of increased atherosclerosis and hypertension in adulthood and should be monitored long-term for these affects.
Investigations: Investigations are performed to exclude other diagnoses, such as infections, and to examine the extent of the illness. The C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated and there is often an anaemia and leucocytosis. A thrombocytopenia may be present in the first week of the illness in addition to the more typical thrombocytosis
Systemic polyarteritis nodosa Systemic polyarteritis nodosa (PAN) was described in 1866 by Kussmaul and Maier. It is a systemic necrotizing vasculitis of medium and small arteries with aneurysm formation. There is cellular infiltration and fibrinoid necrosis of the media. PAN is a multi-system disease. There is a cutaneous form, known as benign cutaneous polyarteritis nodosa (BCPAN) or cutaneous polyarteritis, which has a much better prognosis. Cutaneous polyarteritis may affect the skin, muscles, joints and peripheral nerves and may represent one spectrum of the same disease. Cutaneous PAN requires clinical vigilance for any systemic organ involvement. Systemic PAN is rare in children. A recent multicentre study of all types of paediatric polyarteritis found 110 patients followed in the past five years at 21 different paediatric centres from Europe, Turkey, United States and Brazil.
Figure 4 Skin rash in Kawasaki disease.
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Takayasu arteritis
Diagnosis of PAN: A EULAR/PReS consensus group proposed that diagnosis of PAN requires a biopsy showing a small and medium sized artery necrotising vasculitis or angiographic abnormalities (aneurysms or occlusions) in addition to at least two of the systemic features shown below: Skin involvement (livedo reticularis, tender subcutaneous nodules, other vasculitic lesions) Myalgia or muscle tenderness Systemic hypertension Mononeuropathy or polyneuropathy Abnormal urine analysis and/or impaired renal function (GFR < 50%) Testicular pain or tenderness Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or central nervous system).
Takayasu arteritis (TA) was first described as the ‘‘pulseless disease’’ in 1948. Forty years earlier Takayasu, a Japanese ophthalmologist, described the retinal vessel changes of this disease. TA is a large vessel pan arteritis predominantly affecting the aorta and its main branches. It is a rare condition in children. Unlike HSP and Kawasaki disease it is not a self-limiting disease. It is usually a chronic disease with relapses even whilst on treatment. TA is commonest in females in the third decade. The aetiology of TA is unknown. Symptoms in children include headache, abdominal pain, myalgia, arthralgia, fever, weight loss, limb claudication, cerebrovascular events, angina, and visual disturbance. Clinical examination may reveal hypertension, aortic bruits, reduced or absent peripheral pulses, and blood pressure differences. Investigations reveal a raised ESR, and in some cases a leucocytosis and anaemia. ANCA is usually negative. Chest radiographs may show a wide mediastinum, cardiomegally or an abnormal aortic outline. Arteriography and CT or Magnetic Resonance angiography provide the important imaging required for diagnosis and to monitor disease progression (see Figure 5). Aggressive treatment is indicated to minimise permanent vessel damage. High dose steroids are used to bring the disease into remission. One reported treatment regime in children includes steroids and cyclophosphamide to induce remission followed by methotrexate as maintenance with a tapered steroid dose. Usual maintenance therapy in TA uses combinations of steroid and azathioprine or methotrexate. Antihypertensive medication may be required and surgery may be required to alleviate severe ischaemia.
Aetiology: The aetiology of PAN is unknown. In adults there is an association with previous hepatitis B infection but this is less common in children. Clinical features: There is usually a gradual onset of constitutional symptoms including recurrent pyrexias, weight loss and myalgia. The other symptoms depend on the organs involved, which commonly are the skin, joints, gastrointestinal system and kidney. The cutaneous features possible include painful subcutaneous nodules especially of the feet, palpable purpura, livedo reticularis, necrotic and gangrenous lesions, panniculitis and oedema. Abdominal pain is common which is thought to represent visceral ischemia, and testicular pain is a feature in boys. Arthralgia and arthritis commonly occurs. Renal involvement can manifest as hypertension, proteinuria and haematuria and less commonly for PAN a rapidly progressive nephritis. Neurological involvement commonly presents as a peripheral neuropathy and less commonly as central nervous system features, for example seizures. Cardio-respiratory features are uncommon. The mortality figures for this rare condition vary; the mortality of PAN in children at Great Ormond Street Hospital was quoted as approximately 10%. Investigation and treatment: Laboratory investigations reveal raised acute phase reactants and a leucocytosis. Other findings may include thrombocytosis, anaemia, proteinuria, and haematuria. A positive ANCA is sometimes seen in PAN but its presence usually raises the suspicion of the different diagnosis of microscopic polyangiitis (see below). A recent multicentre survey found 6 out of 47 children with PAN had a positive ANCA. Biopsies and angiograms are used to find evidence of the characteristic vascular changes such as aneurysms. In treating PAN the usual practice is to induce remission with a regime of high dose steroid and cyclophosphamide. This is then followed with maintenance of remission using low dose steroid and azathioprine. Although this is the widely accepted approach it has not tested in a controlled trial. Plasma exchange has been used in severe life threatening cases however conclusions on its effectiveness remain unknown without larger studies. A retrospective review of 5 PAN cases treated with plasma exchange concluded that there was a good response in 4 of the cases.
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Figure 5 Thoracic imaging in Takayasu arteritis showing a very dilated aortic root (arrow).
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ANCA associated vasculitis Wegener’s granulomatosis Wegener’s granulomatosis (WG) is a necrotising granulomatous vasculitis of small blood vessels. The inflammatory infiltrate has polymorphonuclear leucocytes and mononuclear cells. The classical features are respiratory tract granulomas, a widespread small vessel vasculitis and a necrotising glomerulonephritis. Friedrich Wegener described the condition first in 1936. The cause is unknown. The ANCA investigation is usually positive and characteristically it is cANCA. Indeed the ANCA are even suggested to play a role in the aetiology because they have been shown to stimulate inflammation. EULAR/PReS recently published consensus criteria for the classification of WG in children to take into account the paediatric WG findings and investigations. These classification criteria are currently being validated and are as follows: Three of the following six features: Abnormal urinalysis (haematuria and/or significant proteinuria) Granulomatous inflammation on biopsy (if a kidney biopsy is done it characteristically shows necrotising pauci-immune glomerulonephritis). Nasal sinus inflammation Subglottic, tracheal, or endobronchial stenosis Abnormal chest x ray or CT PR3 ANCA or cANCA staining Clinical features: Children usually present with symptoms of the ears, nose and sinuses and constitutional symptoms of fever, lethargy and weight loss. Inflammatory changes of the upper respiratory tract may result in epistaxis, sinusitis, cough, and nasal septum perforation. Chondritis of the bridge of the nose leads to a classic saddle nose deformity. Granulomas may be visible on inspection of the nasal mucosa, oral ulcers may occur, and the possible ear pathology includes otitis media and deafness. Lesions of the tracheobronchial airways cause subglottic stenosis and stridor (see Figure 6). Biopsies of these lesions at laryngobronchoscopy can help to diagnose WG. Involvement of the lower respiratory tract may be asymptomatic and detected on imaging or may result in symptoms of cough, respiratory distress or haemoptysis.
Figure 7 Vasculitic skin lesions in Wegener’s granulomatosis.
Skin involvement may result in erythema, purpuric lesions, urticaria, ulcerative or necrotic lesions (see Figure 7). Skin involvement affects up to 50% during the course of the disease. In two series glomerulonephritis was reported in 61% and 88% of cases during the course of the illness. Orbital granulomatous pseudotumours can result in proptosis and these orbital lesions may be biopsied to confirm the diagnosis. Ocular inflammation has also been described including episcleritis/scleritis, conjunctivitis, uveitis, retinal vasculitis and optic neuritis. The other possible symptoms include a transient arthritis which typically resolves with control of the WG without long term joint damage. Cardiac involvement is rare but may include pericarditis, pancarditis, coronary arteritis and valvulitis. Venous thromboembolism may occur. Cranial nerve palsies, peripheral neuropathy, and cerebral infarction may also occur. Gastrointestinal disease can cause bowel perforation and involvement of the anus and rectum. Treatment: WG can be a devastating vasculitis, which typically flares with the reduction of immunosuppression. The mortality has been reported as high as 12% (39). Patients are usually treated with high dose steroids and cyclophosphamide to induce remission followed by lower dose steroids and azathioprine to maintain remission. There is a considerable risk of infection with
Figure 6 Bronchoscopy demonstrating narrowing of the left main bronchus in Wegener’s granulomatosis.
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cyclophosphamide and paediatric patients are currently being enrolled in a EUVAS (European Vasculitis Study Group) clinical trial of mycophenolate mofetil versus cyclophosphamide to induce remission in WG.
mofetil, rituximab, anti-TNF-a and anakinra and with international trials progress will be made. Meanwhile, at the clinical presentation level, it is the varied and possible constitutional nature of the clinical features which highlight the need to consider a diagnosis of vasculitis in any child with unexplained raised inflammatory markers and to perform appropriate investigations often in a specialist centre.
Microscopic polyangiitis Microscopic polyangiitis (MPA) is a small vessel necrotising nongranulomatous vasculitis. It is pauci-immune, showing few or no immune deposits. MPA affects arterioles, venules and capillaries. Microscopic polyangiitis was previously known as microscopic polyarteritis. The pathology is similar to WG but without granulomas. The main feature is the renal disease and this condition may encompass cases of what was previously known as idiopathic crescentic glomerulonephritis. Clinically there is a focal segmental necrotising glomerulonephritis and often a pulmonary capillaritis. It is commonly associated with p-ANCA positivity or less commonly c-ANCA positivity. One study found that 9 of 10 cases of paediatric MPA were ANCA positive (5 positive for MPOANCA, 4 positive for PR3-ANCA). These ANCA results in MPA demonstrated a very strong staining pattern. In contrast in the same study only 6 of 16 PAN cases showed ANCA positivity and these had mild staining patterns. The treatment of MPA is similar to that of Wegener’s granulomatosis with cyclophosphamide, steroids, azathioprine and plasma exchange for very severe cases.
Conflict of interest of authors None.
FURTHER READING Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, Silverman ED. Clinical features and outcome of pediatric Wegener’s granuolomatosis. Arthritis Rheum 2007; 57: 837e44. Bakkaloglu A, Ozen S, Baskin E, et al. The significance of antineutrophil antibody in microscopic polyangitis and classic polyarteritis nodosa. Arch Dis Child 2001; 85: 427e30. Brogan PA, Bose A, Burgner D, et al. Kawasaki disease:an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child 2002; 86: 286e90. Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of pediatric rheumatology. 5th Edn. Elsevier Saunders, 2005. Chartapisak W, Opastiraku S, Willis NS, Craig JC, Hodson EM. Prevention ¨nlein purpura: and treatment of renal disease in Henoch-Scho a systematic review. Arch Dis Child 2009; 94(2): 132e7. Dillon MJ. Vasculitis treatment e new therapeutic approaches. Eur J Pediatr 2006; 165: 351e7. Eleftheriou D, Brogan PA. Vasculitis in children. Best Pract Res Clin Rheumatol 2009; 23: 309e23. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics 2007; 120: e1434e40. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic fever, Endocarditis, and Kawasaki disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004; 114: 1708e33. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicentre survey of 110 children. J Pediatr 2004; 145: 517e22. Ozen S, Duzova A, Bakkaloglu A, et al. Takayasu arteritis in children: preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate. J Pediatr 2007; 150: 72e6. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PreS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 2006; 65: 936e41. Tizard EJ, Dillon MJ. Wegener’s granulomatosis, polyarteritis nodosa, Behc¸et’s disease and relapsing polychondritis. Textbook of pediatric dermatology, vol. 2. 2nd Edn. Blackwell publishing, 2006. ¨nlein purpura. Arch Dis Child Tizard EJ, Hamilton-Ayres MJJ. Henoch-Scho Educ Pract Ed 2008; 93: 1e8. Zwerina J, Eger G, Englbrecht M, Manger B, Schett G. Churg-Strauss syndrome in childhood:a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 2008 [Epub article in press].
Churg-Strauss syndrome Churg and Strauss described this condition in 1951. It is extremely rare but does occur in children. It is a necrotising granulomatous vasculitis of small arteries and veins with an eosinophillic infiltrate. The aetiology is unknown. Children affected are usually already known to have asthma or allergic rhinitis and then develop worsening symptoms with pyrexias, eosinophilia, and pulmonary infiltrates. Clinical manifestations may include hypertension, pneumonitis, skin nodules, purpura, livedo reticularis, cardiac failure, nephritis and neuropathy. Churg Strauss syndrome is classified as an ANCA associated vasculitis however a recent study reported only 25% of childhood cases were positive. The treatment of CSS includes steroids, cyclophosphamide and plasma exchange.
Summary This review highlights that there are many unanswered questions in the field of paediatric vasculitis. With regards to HSP continued research is required to identify firstly ways to reduce the number of cases developing renal disease and secondly how to treat HSP renal disease. In Kawasaki disease methods to recognise the condition early are paramount with treatment having been proven to reduce the cardiovascular morbidity. Many of the knowledge limitations of the other vasculitides described are a result of the very small patient numbers. Polyarteritis nodosa, Takayasu arteritis and the ANCA associated vasculitides all have a significant morbidity and mortality which also limits the scope for trying new treatment methods, even if the current routine approaches have not themselves been through controlled trials. Hopefully with the development of newer immunosuppressant agents such as mycophenolate
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Practice points C
C
C
C
Vasculitis in children may present with a wide range of clinical features including skin rash, fever, malaise, weight loss, abdominal pain, hypertension, proteinuria, arthritis, myalgia, and features of any of the major organ systems. ANCA may be useful in the diagnosis and follow up of children with Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. If children with HSP have significant renal involvement discuss with a paediatric nephrologist for consideration of renal biopsy and possible immunosuppression.
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C
C
C
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Children who have had HSP nephritis should have life long follow up. Treat Kawasaki disease with immunoglobulin without delay to reduce the incidence of coronary artery aneurysms. Consider a diagnosis of Kawasaki disease even if fewer than the required features are present particularly in very young patients, and in cases when the features do not all occur simultaneously. Consider a diagnosis of one of the rarer childhood vasculitides in children with persistent unexplained raised inflammatory markers and refer for investigation often to a specialist centre.
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