Classification of Vasculitis in Childhood

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1 Review Article Classification of Vasculitis in Childhood Ezgi D. Batu, Yelda Bilginer Abstract Vasculitides are heterogeneous diseases characterized by inflammation in the vessel wall. The primary systemic vasculitides in childhood are quite uncommon except for Ig A vasculitis/henoch-schönlein purpura and Kawasaki disease. Besides the relative frequency of vasculitis subtypes, clinical characteristics and prognosis also tend to differ between children and adults. Because of the heterogeneous nature of vasculitis, it is difficult to identify proper subgroups. The nomenclature systems (names and definitions), classification, and diagnostic criteria are used to categorize vasculitides and these have evolved and have been revised with the substantial improvement in our understanding of vasculitis pathogenesis through advanced diagnostic tests and genetic studies. In the process of revision, the eponyms were replaced by more descriptive terms, new vasculitis categories were defined, the radiologic technologies and biomarkers (such as acute phase reactants and anti-neutrophil cytoplasmic antibodies) were incorporated, and the categorization depended on vessel size, type, and etiopathogenesis. The Chapel Hill Consensus Conferences 2012, the American College of Rheumatology criteria and the Ankara 2008 criteria constitute the major attempts for categorization and classification of vasculitides. The Diagnostic and Classification Criteria for Vasculitides study is currently underway to develop and validate diagnostic criteria and to improve classification criteria. Further multicenter prospective studies will help to incorporate the classification systems more into the clinical practice. Here, we review the current nomenclature, classification system, and classification criteria of vasculitides especially in childhood. Key words: Vasculitis, classification, children, CHCC 2012, Ankara 2008 criteria, ACR criteria Division of Rheumatology, Department of Paediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey Corresponding Author: Yelda Bilginer, Hacettepe University Faculty of Medicine Department of Paediatrics, Divison of Rheumatology, Ankara, Turkey yeldabilginer@yahoo.com Received: Mar 18, 2016 Accepted: Mar 28, 2016 Ann Paediatr Rheum 2016;5:1-10 DOI: /apr Introduction Vasculitides are heterogeneous diseases characterized by changes in vessel wall as a consequence of an inflammatory process. Clinical characteristics depend on the size, type, and location of the vessels involved. Primary vasculitides are regarded to be more common in adults than children [1-3]. The estimated incidence for pediatric vasculitides is around 50 cases per 100,000 children annually [4]. Although the overall incidence is

2 2 Batu ED et al. low in children, certain types of vasculitides exclusively occur in childhood such as immunoglobulin A vasculitis/henoch- Schönlein purpura (IgAV/HSP) and Kawasaki disease (KD) [5]. Besides the relative frequency of vasculitis subtypes, clinical characteristics and prognosis also tend to differ between children and adults. Because of the heterogeneous nature of vasculitis and limited knowledge about their causes, it is difficult to identify proper subgroups. There are different categorization attempts and criteria sets for vasculitis. A nomenclature system forms a framework for developing classification/diagnostic criteria by providing names and definitions [6]. Classification criteria are mainly for defining more homogeneous patient groups for research purposes [7] while diagnostic criteria are applied to the individual patient to diagnose the disease by ruling out other mimicking conditions [8]. In fact, we could say that unlike classification criteria, diagnostic criteria should be both 100% sensitive and specific [9]. In the case of primary vasculitides, the diagnosis does not rely on a single pathognomonic test thus the term classification criteria seems more appropriate than diagnostic criteria [10]. Here, we review the current nomenclature, classification system, and classification criteria of vasculitides in childhood. Progress in vasculitis nomenclature and classification In 1994, an international conference was held in Chapel Hill (CHCC, Chapel Hill Consensus Conference) to develop a nomenclature system for vasculitides and they distinguished vasculitis by the size of the vessels predominantly affected [11]. The International CHCC convened again in 2012 and they modified the nomenclature system by adding some new categories such as variable vessel vasculitis (VVV) and singleorgan vasculitis (Table 1) [12]. The American College of Rheumatology (ACR) proposed a series of classification criteria for vasculitis in adults in 1990 [13, 14]. However, the ACR criteria set did not refer to anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), excluded microscopic polyangiitis (MPA) as a disease category, omitted KD, and has never been validated in children [13-18]. With this background, preliminary classification criteria were proposed in 2005 for some of the most common vasculitides in childhood such as HSP (now Table 1. Classification of vasculitis (adapted from reference 12). I II III IV V VI VII Large-vessel vasculitis (LVV) Takayasu s arteritis (TAK) Giant cell arteritis (GCA) Medium-vessel vasculitis (MVV) Polyarteritis nodosa (PAN) Kawasaki disease (KD) Small-vessel vasculitis (SVV) A. Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) Microscopic polyangiitis (MPA) Granulomatosis with polyangiitis (Wegener granulomatosis) (GPA (WG)) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA (CSS)) B. Immune complex SVV Anti-glomerular basement membrane (anti- GBM) disease Cryoglobulinemic vasculitis (CV) IgA vasculitis (Henoch-Schönlein) (IgAV (HSP)) Hypocomplementemic urticarial vasculitis (HUV) (anti-c1q vasculitis) Variable vessel vasculitis Behçet s disease (BD) Cogan s syndrome (CS) Single-organ vasculitis Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis associated with systemic disease Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis Others Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others Annals of Paediatric Rheumatology Year 2016 Volume:5 Issue:1 1-10

3 Vasculitis classification 3 IgAV), KD, polyarteritis nodosa (PAN), Wegener granulomatosis (WG) (now granulomatous polyangiitis [GPA]), and Takayasu arteritis (TA) [19]. These criteria were validated at the 2008 Ankara Consensus Conference by endorsement of European League Against Rheumatism (EULAR), Pediatric Rheumatology European Society (PRES), and the Pediatric Rheumatology International Trials (PRINTO) [19-21]. Both ACR and Ankara 2008 criteria were derived from a large database compared to cases with other vasculitis as controls. This information implies that these criteria sets should be used to discriminate the subclass of disease in cases with a prior knowledge of vasculitis [10]. The main characteristics of the ACR [15-18] and Ankara 2008 criteria [20] are summarized in Table 2. In 2010, EULAR established an expert panel to identify deficiencies in the ACR criteria and CHCC 1994 nomenclature [22]. They have mentioned 17 points for development of revised classification and diagnostic criteria [22]. These points were mainly about the definitions, nosology, biopsy, laboratory testing (e.g., use of ANCA), diagnostic radiology, and the research agenda. Most of these points had already been incorporated in the Ankara 2008 criteria [20] and CHCC 2012 met the need for a classification tree [12]. Currently, there are no diagnostic criteria available for the primary systemic vasculitis and classification criteria are used for diagnosis in clinical practice, albeit with a low sensitivity [23]. To develop and validate diagnostic criteria and to improve classification criteria, the diagnostic and classification criteria for vasculitides (DCVAS) study is currently underway which promises further progress in the area of vasculitis criteria [24]. CHCC 2012: categorization of vasculitis With the improved understanding of the etiopathogenesis, the categorization, names, and definitions for vasculitis were updated in CHCC 2012 (Table 1) [12]. Most of the eponyms were replaced by the terms that describe the pathogenesis of the disease. In addition, new vasculitis categories were included in order to separate VVV, single-organ vasculitis, vasculitis associated with systemic disease, and vasculitis associated with probable etiology. The categorization mainly depends on the size of the predominantly involved vessel; however, in CHCC 2012, they also took into account the pathogenesis especially while subcategorizing small-vessel vasculitis (SVV) [12]. There are some shortcomings of CHCC First of all, the categorization still depends on mainly on vessel size; however, the vessel involvement of different vasculitis categories may overlap. Besides, it may be difficult to define the size of the involved vessel through pathologic examination in some cases [10]. There are a group of patients who are classified as having AAV with no detectable ANCA. It is challenging to fit these patients into any category in CHCC 2012 [10]. In addition, recently, new diseases have been defined in which monogenic defects result in vasculopathy such as deficiency of adenosine deaminase 2 (DADA2) [25, 26] and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) [27]. These diseases may be classified under the category of vasculitis associated with a probable cause but do not perfectly fit. There could be a separate subcategory called monogenic vasculopathies. Large-vessel vasculitis (LVV) Large-vessel vasculitis (LVV) mainly affects the aorta and its large branches and the major subcategories of LVV are TA and giant cell arteritis (GCA) [12]. TA is defined as granulomatous aorta arteritis usually occurring before age of 50 years [12] and it is the only LVV referred to in current pediatric classifications [20]. GCA is defined as granulomatous aorta arteritis predominantly involving the carotid and vertebral arteries occurring after age 50 years and often associated with polymyalgia rheumatica [12]. GCA almost never occurs during childhood [5]. The major discriminating factor between TA and GCA appears to be the age of patient at LVV onset in CHCC 2012 [12]. In Ankara 2008 criteria (Table 2), angiographic anomalies criterion was modified to include imaging modalities such as computerized tomography (CT) and magnetic resonance imaging and was made a mandatory criterion [20]. Hypertension which may be the only symptom in children and elevation in acute phase reactants which may warn the physician before the symptoms settle were also included in the criteria. With all these modifications, the criteria had a sensitivity of 100% and specificity of 99% in children [20]. DOI: /apr

4 4 Batu ED et al. Table 2. ACR criteria (15-18) versus Ankara 2008 criteria (20) for vasculitis classification. Vasculitis IgA vasculitis/ Henoch Schönlein purpura Polyarteritis nodosa Granulomatous polyangiitis/ Wegener granulomatosis Takayasu arteritis Classification criteria [reference number] ACR criteria (15-18) Ankara 2008 criteria (20) 2 of the following: 20 years of age at disease onset Palpable purpura Acute abdominal pain Biopsy showing granulocytes in the wall of small arterioles/venules 3 of the following 10 criteria: Granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy Arteriographic abnormalities Livedoreticularis Myalgia Diastolic blood pressure >90 mmhg Mono- or polyneuropathy Elevated blood urea nitrogen or creatinine Testicular pain/tenderness Hepatitis B reactants Weight loss >4 kg 2 of the following: Abnormal urinary sediment (red cell casts or >5 red blood cell per high power field) Abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates) Oral ulcers or nasal discharge Granulomatous inflammation on biopsy 3 of the following: Arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal, upper or lower extremities Decreased brachial artery pulse Claudication of an extremity >10 mmhg difference in systolic blood pressure between arms A bruit over subclavian arteries or the aorta Age at disease onset 40 years a For purpura with atypical distribution, a demonstration of an IgA deposit in a biopsy is required. Purpura or petechia (mandatory) with lower limb predominance a plus one of four: Abdominal pain Histopathology (predominant IgA deposit in a biopsy) Arthritis or arthralgia Renal involvement Histopathology or angiographic abnormalities (mandatory) plus one of five: Skin involvement Myalgia/muscle tenderness Hypertension Peripheral neuropathy Renal involvement At least three of six: Histopathology (granulomatous inflammation) Upper airway involvement Laryngo-tracheo-bronchial stenosis Pulmonary involvement (chest X-ray or CT showing the presence of nodules, cavities, or fixed infiltrates) ANCA positivity Renal involvement Angiography (conventional, CT or MRI) of the aorta or its major branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion or thickened arterial wall (mandatory) plus one of five: Pulse deficit or claudication Four limbs blood pressure discrepancy >10 mmhg Bruits Hypertension (>95 percentile for height) Elevated acute phase reactants Annals of Paediatric Rheumatology Year 2016 Volume:5 Issue:1 1-10

5 Vasculitis classification 5 Medium-vessel vasculitis (MVV) Medium-vessel vasculitis (MVV) predominantly targets medium-sized arteries which are defined as the main visceral arteries and their branches; however, it can affect any size artery [12]. It has two major subcategories as PAN and KD. PAN is defined as the necrotizing vasculitis of medium/ small-sized arteries without glomerulonephritis or vasculitis in arterioles, venules, and capilleries and it is not associated with ANCA [12]. Thus, kidney involvement is due to the vasculitis of lobar and arcuate arteries, not glomerular capillaries. The main revision in CHCC 2012 was the addition of negative ANCA to the definition [12]. PAN is the third most common vasculitis after IgAV/HSP and KD in children [28, 29]. Due to vaccination protocols, hepatitis B serology positivity is unusual in pediatric PAN [28]. Furthermore, if PAN-like vasculitis is demonstrated to be related to hepatitis B infection, it should be classified under the category of vasculitis associated with probable etiology [12]. Because of this, this criterion (hepatitis B serology) was removed while forming the Ankara 2008 criteria for pediatric PAN [20]. After designating the typical histopathology or angiographic abnormalities as a mandatory criterion and with the removal of the criteria for the signs and symptoms of vasculitis in specific organ systems and testicular pain/tenderness; pediatric PAN classification criteria took its final form (Table 2) [20]. It had a sensitivity of 89.6% and specificity of 99.6% in children [20]. KD is defined as a mucocutaneous lymph node syndrome with MVV often involving the coronary arteries [12]. It may also involve other medium-sized ateries, but only rarely. KD is predominantly a childhood systemic vasculitis [30]. For the diagnosis of KD, the criteria set formed by the American Heart Association was used [31]. A child is diagnosed as having KD if she/he has fever (for five or more days) plus four of the following 5 criteria: conjunctivitis (bilateral, bulbar, non-suppurative), lymphadenopathy (cervical, often >1.5 cm), rash (polymorphous, no vesicles or crusts), changes in lips and oral mucosa (red cracked lips; strawberry tongue; or diffuse erythema of oropharynx), and changes in extremities (erythema and edema of palms/soles; peeling of skin from fingertips) [31]. According to the Ankara 2008 criteria, a patient is classified as having KD if she/he has fever persisting for at least five days (mandatory criterion) plus four of the following five criteria: changes in the peripheral extremities and perianal area, polymorphous exanthema, bilateral conjunctival injection, changes of lips and oral cavity and/or injection of oral and pharyngeal mucosa, and cervical lymphadenopathy [20]. When coronary artery involvement is demonstrated by echocardiography/angiography, children with fewer than four criteria can be diagnosed with KD [31]. In addition, we should keep in mind that infants may have fewer classical signs of KD and patients may present with atypical features such as arthritis, aseptic meningitis, pneumonitis, uveitis, gastroenteritis, meatitis, and otitis [32, 33]. Small-vessel vasculitis (SVV) In CHCC 2012, SVV was subclassified into two major divisions depending on the pathogenesis: AAV and immune complex SVV [12]. After the discovery of ANCA in 1982 [34], in vitro experiments and animal models documented that ANCA could activate neutrophils and monocytes to mediate vascular inflammation [35-37]. In CHCC 2012, AAV was defined as necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels associated with myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA [12]. In addition, a prefix should be added to indicate ANCA reactivity [12]. AAV has three subcategories as MPA, GPA/WG, and eosinophilic granulomatosis with polyangiitis/churg-strauss syndrome (EGPA/CSS). MPA was not classified as a separate entity prior to CHCC 2012 [12]. AAV are rare in childhood with an incidence of 2.4 per 1,000,000 children annually and GPA/WG is the most frequently diagnosed one [2]. MPA is defined as necrotizing vasculitis of small/medium-sized vessels and it is frequently associated with pauciimmune glomerulonephritis and ANCA [12]. On the other hand, GPA/WG is commonly associated with granulomatous inflammation of the respiratory tract besides small/ medium-vessel vasculitis, pauci-immune glomerulonephritis, and ANCA association [12]. Currently clinical methods have demonstrated that at least 80-90% of MPA (mostly MPO- ANCA) and GPA/WG (mostly PR3-ANCA) patients have DOI: /apr

6 6 Batu ED et al. ANCA [38]. A recent genome-wide association study has provided evidence for subclassification of this disease group (MPA and GPA/WG) by ANCA specificity (PR3 or MPO) than clinical phenotype [39]. Certain modifications of the ACR criteria were made while forming pediatric classification criteria for GPA/WG. In Ankara 2008 criteria (Table 2), ANCA positivity was added as a criterion [20]. Since subglottic stenosis has been reported to be more common in pediatric patients [40, 41]; the presence of subglottic, tracheal, or endobronchial stenosis was also added to the group of criteria [20]. In addition, as a result of progresses in radiology techniques, chest CT was added to the definitions based on radiologic imaging [20]. In its final form, this criteria set had a sensitivity of 93.3% and specificity of 89.2% [20]. EGPA/CSS is defined as a necrotizing small/medium vessel vasculitis often involving the respiratory tract together with eosinophil-rich granulomatous inflammation [12]. Approximately 40% of EGPA/CSS patients have ANCA [38]. EGPA/CSS is usually characterized by late-onset asthma and frequent non-infectious sinusitis; the rhinitis and sinusitis of EGPA/CSS is often described as allergic [42-44]. Immune complex SVV is characterized by moderate to marked deposits of Ig and/or complement components predominantly in the walls of small vessels [12]. IgAV/HSP is the most common form of pediatric vasculitis while other immune complex SVV are quite rare in childhood [45, 46]. IgAV/HSP is characterized by arthritis and frequent skin and gastrointestinal vasculitis with IgA deposits and possible IgA nephropathy [12]. Since an abnormal glycosylation of IgA1 hinge region lead to disease process, the descriptive term IgA vasculitis replaced the eponym Henoch-Schönlein [12]. During the revision of classification criteria in Ankara 2008 conference, palpable purpura was made a mandatory criterion (Table 2) [20]. The IgA depositis are defined as predominant to differentiate IgAV/HSP from other diseases with IgA deposits [20, 47]. Joint involvement was more common in children than adults with IgAV/HSP [20] and renal involvement is the main cause for late morbidity and mortality occurring approximately 40% of children with IgAV/HSP within six weeks of presentation [48]. Thus, arthritis and renal involvement were both included in the new criteria set. Age criterion was deleted. The sensitivity and specificity of Ankara 2008 criteria for IgAV/HSP was found as 100% and 87%, respectively [20]. Recently, Hocevar et al have compared the performance of the Ankara 2008 criteria and the ACR criteria for IgAV/HSP for the first time in adult patients with vasculitis [49]. The Ankara 2008 criteria had a higher sensitivity (99.2% vs 86.8%) and specificity (86% vs 81%) than the ACR criteria. Variable vessel vasculitis (VVV) Behçet s disease (BD) and Cogan s syndrome were included in this category and VVV can affect the vessels of any size and type [12]. Cogan s syndrome is a very rare multisystemic inflammatory disease and it is characterized by rapid onset of non-vasculitic ocular inflammatory lesions and inner ear symptoms such as deafness and vertigo [50]. Approximately 10% of these patients develop vasculitis mainly in the form of LVV and systemic symptoms occur in 50% [50, 51]. BD is characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and central nervous system inflammatory lesions [12]. Most BD cases are clustered along the historic Silk Road from Japan to Mediterranean countries [52] with the highest prevalence being reported in Iran and Turkey [53, 54]. It is estimated that 1-2% of BD patients are children [55]. There are more than 15 sets of diagnostic/classification criteria for BD [56]. According to the International Study Group (ISG) criteria set which was presented in 1990 and 1992 [57, 58]; diagnosing BD requires the presence of oral aphthosis (mandatory) plus two of the following four features: genital aphthosis, skin manifestations (pseudofolliculitis, erythema nodosum), ophthalmologic manifestations, and positive pathergy test. However, many BD patients were not classified as having BD according to the ISG criteria since it had low sensitivity. Thus, a new criteria set called the International Criteria for BD (ICBD) was created in 2006 [59, 60] and revised in 2014 [61]. In the revised ICBD, the patient is classified as having BD if she/he gets four or more points [61]. The patient gets two points for each of oral aphthosis, genital aphthosis, ophthalmologic involvement; and one point for each of skin, neurologic, and vascular manifestations and positive pathergy Annals of Paediatric Rheumatology Year 2016 Volume:5 Issue:1 1-10

7 Vasculitis classification 7 test. ICBD was found to be more sensitive than the ISG criteria although at the expense of a small decrease in specificity [57]. Recently, Nanthapisal et al compared the performance of ISG criteria and ICBD in pediatric BD cases and showed that ICBD was more sensitive than the ISG criteria (14.7% vs 80.4%) [62]. The specificity could not be measured because of the lack of a control group. These criteria sets were mainly developed from studies on adult patients and none has been validated in children. However, BD characteristics differ between children and adults. Besides, the disease is not complete before 16 years of age in more than 80% of patients [63]. With this background, most recently, the pediatric BD (PEDBD) group has determined new classification criteria for children with BD [64]. Pathergy test was excluded and all symptom categories have equal weight in this criteria set. According to the PEDBD criteria, a patient is classified as having BD if she/he had 3 of the following characteristics: oral aphthosis ( 3 attacks/ year), genital aphthosis (typical with scars), skin involvement (necrotic folliculitis, acneiform lesions, erythema nodosum), neurologic involvement (except isolated headaches), ocular manifestations (anterior uveitis, posterior uveitis, retinal vasculitis), and vascular signs (venous thrombosis, arterial thrombosis, arterial aneurysm) [64]. Single-organ vasculitis Single-organ vasculitis is defined as vasculitis in a single organ with no features indicating a limited form of a systemic vasculitis [12]. Before classifying a patient as having singleorgan vasculitis, the patient should be followed for a certain time period (minimum six months) to rule out progression to systemic vasculitis [65]. The single-organ vasculitis may also be primary or secondary in etiology and subcategorization in that manner may help with the guidance of proper treatment. Other vasculitis Other categories are vasculitis associated with systemic disease and vasculitis associated with probable cause [12]. These are mainly secondary vasculitis and the causes include systemic diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus), cancer, drug exposure, and infection (e.g., hepatitis viruses) [10]. With the revision in the classification tree in CHCC 2012 [12], hepatitis B-associated PAN-like vasculitis is no longer classified in the subcategory of PAN, but it is classified in vasculitis associated with probable cause category [12]. This distinction is based mainly on etiopathogenesis and it is highly relevant since these cases can benefit from a causebased management [66]. An autosomal recessive disorder called DADA2 has recently been described and it causes a vasculopathy with autoinflammatory features associated with mutations in the CECR1 gene [25, 26]. The phenotype of DADA2 varies from only cutaneous lesions to full-blown systemic disease which may overlap with the spectrum of PAN [25, 26, 67]. Another recently described monogenic disease is SAVI caused by mutations in the TMEM173 gene and it causes a severe cutaneous vasculopathy leading to extensive tissue loss [27]. These monogenic vasculopathies may be classified under the category of vasculitis associated with probable cause. However, a separate subcategory like monogenic vasculopathies could be more appropriate. Conclusion There have been important advances in diagnostic technology and improvement in our understanding of etiopathogenesis in the area of vasculitis. Based on this, vasculitis nomenclature and classification system also evolved. CHCC 2012 nomenclature and classification system which depends both on the involved vessel size and etiopathogenesis, remains the most practical way to categorize vasculitis. Further multicenter prospective studies will help to incorporate the classification systems more into the clinical practice. Diagnostic criteria are also very important in clinics for patients with vasculitis and this will hopefully be achieved by DCVAS study [24]. Conflict of interest: None of the authors received financial support and there are no potential conflicts of interest. Funding: No source of funding for this work. References 1. Eleftheriou D, Melo M, Marks SD, Tullus K, Sills J, Cleary G, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology (Oxford) 2009; 48: Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schonlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 2002; 360: DOI: /apr

8 8 Batu ED et al. 3. Watts RA SD. Epidemiology in vasculitis. In: Ball GV BS ed. Vasculitis. Oxford: Oxford University Press. 2008: Rowley AH OS, Sundel RP, et al. A clinician s pearls and myths in rheumatology. London: Springer, Ozen S. Problems in classifying vasculitis in children. Pediatr Nephrol 2005; 20: Jennette JC. Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 2013; 17: Jennette JC, Falk RJ. Do vasculitis categorization systems really matter? Curr Rheumatol Rep 2000; 2: Hunder GG. The use and misuse of classification and diagnostic criteria for complex diseases. Ann Intern Med 1998; 129: Doria A, Mosca M, Gambari PF, Bombardieri S. Defining unclassifiable connective tissue diseases: incomplete, undifferentiated, or both? J Rheumatol 2005; 32: Mahr A, de Menthon M. Classification and classification criteria for vasculitis: achievements, limitations and prospects. Curr Opin Rheumatol 2015; 27: Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65: Bloch DA, Michel BA, Hunder GG, McShane DJ, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods. Arthritis Rheum 1990; 33: Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990; 33: Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990; 33: Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener s granulomatosis. Arthritis Rheum 1990; 33: Lightfoot RW, Jr., Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990; 33: Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Henoch- Schonlein purpura. Arthritis Rheum 1990; 33: Bayrakci US BE, Ozen S. Treatment of Henoch-Schönlein purpura: what evidence do we have? Int J Clin Rheumatol 2010; 5: Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara Part II: Final classification criteria. Ann Rheum Dis 2010; 69: Ruperto N, Ozen S, Pistorio A, Dolezalova P, Brogan P, Cabral DA, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara Part I: Overall methodology and clinical characterisation. Ann Rheum Dis 2010; 69: Basu N, Watts R, Bajema I, Baslund B, Bley T, Boers M, et al. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis 2010; 69: Rao JK, Allen NB, Pincus T. Limitations of the 1990 American College of Rheumatology classification criteria in the diagnosis of vasculitis. Ann Intern Med 1998; 129: Craven A, Robson J, Ponte C, Grayson PC, Suppiah R, Judge A, et al. ACR/EULAR-endorsed study to develop Diagnostic and Classification Criteria for Vasculitis (DC- VAS). Clin Exp Nephrol 2013; 17: Annals of Paediatric Rheumatology Year 2016 Volume:5 Issue:1 1-10

9 Vasculitis classification Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014; 370: Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370: Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med 2014; 371: Ozen S, Anton J, Arisoy N, Bakkaloglu A, Besbas N, Brogan P, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children.j Pediatr 2004; 145: Ozen S, Bakkaloglu A, Dusunsel R, Soylemezoglu O, Ozaltin F, Poyrazoglu H, et al. Childhood vasculitides in Turkey: a nationwide survey. Clin Rheumatol 2007; 26: Everett ED. Mucocutaneous lymph node syndrome (Kawasaki disease) in adults. JAMA 1979; 242: Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and longterm 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. Circulation 2004; 110: Eleftheriou D, Batu ED, Ozen S, Brogan PA. Vasculitis in children. Nephrol Dial Transplant 2015; 30: Guillevin L, Pagnoux C, Seror R, Mahr A, Mouthon L, Le Toumelin P, et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore) 2011; 90: van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener s granulomatosis. Lancet 1985; 1: Primo VC, Marusic S, Franklin CC, Goldmann WH, Achaval CG, Smith RN, et al. Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis. Clin Exp Immunol 2010; 159: Savage CO. Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Clin Exp Immunol 2011; 164: Xiao H, Heeringa P, Hu P, Liu Z, Zhao M, Aratani Y, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Inves 2002; 110: Jennette JC FR. ANCA vasculitis: microscopic polyangiitis, Wegener s granulomatosis and Churg Strauss syndrome. Pathol Case Rev 2007; 12: Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367: Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol 2002; 17: Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt RY, et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993; 122: Bottero P, Bonini M, Vecchio F, Grittini A, Patruno GM, Colombo B, et al. The common allergens in the Churg- Strauss syndrome. Allergy 2007; 62: Chumbley LC, Harrison EG, Jr., DeRemee RA. Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc 1977; 52: Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984; 63: Allen DM, Diamond LK, Howell DA. Anaphylactoid purpura in children (Schonlein-Henoch syndrome): review with a follow-up of the renal complications. Am J Dis Child 1960; 99: Gedalia A. Henoch-Schonlein purpura. Curr Rheumatol Rep 2004; 6: Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, et al. EULAR/PReS endorsed consensus criteria for DOI: /apr

10 10 Batu ED et al. the classification of childhood vasculitides. Ann Rheum Dis 2006; 65: Kawasaki Y. The pathogenesis and treatment of pediatric Henoch-Schonlein purpura nephritis. Clin Exp Nephrol 2011; 15: Hocevar A, Rotar Z, Jurcic V, Pizem J, Cucnik S, Vizjak A, et al. IgA vasculitis in adults: the performance of the EULAR/PRINTO/PRES classification criteria in adults. Arthritis Res Ther 2015; 18: Singer O. Cogan and Behcet syndromes. Rheum Dis Clin North Am 2015; 41:75-91, viii. 51. Kessel A, Vadasz Z, Toubi E. Cogan syndrome--pathogenesis, clinical variants and treatment approaches. Autoimmun Rev 2014; 13: Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behcet s disease. Arch Ophthalmol 1982; 100: Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, et al. Prevalence of Behcet s disease in Istanbul, Turkey. Intern J Dermatol 2003; 42: Davatchi F, Chams-Davatchi C, Shams H, Nadji A, Faezi T, Akhlaghi M, et al. Adult Behcet s disease in Iran: analysis of 6075 patients. Intern J Rheum Dis 2016; 19: Ozen S. The spectrum of vasculitis in children. Best Pract Res Clin Rheumatol 2002; 16: Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, Shahram F, Shams H, Nadji A, et al. The saga of diagnostic/classification criteria in Behcet s disease. Intern J Rheum Dis 2015; 18: Criteria for diagnosis of Behcet s disease. International Study Group for Behcet s Disease. Lancet 1990; 335: Evaluation of diagnostic ( classification ) criteria in Behcet s disease--towards internationally agreed criteria. The International Study Group for Behcet s disease. Br J Rheumatol 1992; 31: Disease ITftRotICf Bs. Evaluation of the international criteria for Behçet s disease (ICBD). Clin Ex Immunol 2006; 24:S Disease ITftRotICf Bs. Revision of the international criteria for Behçet s disease (ICBD) Clin Exp Rheumatol 2006; 24:S International Team for the Revision of the International Criteria for Behcet s D. The International Criteria for Behcet s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28: Nanthapisal S, Klein NJ, Ambrose N, Eleftheriou D, Brogan PA. Paediatric Behcet s disease: a UK tertiary centre experience. Clin Rheumatol 2016, doi /s z 63. Kotter I, Vonthein R, Muller CA, Gunaydin I, Zierhut M, Stubiger N. Behcet s disease in patients of German and Turkish origin living in Germany: a comparative analysis. J Rheumatol 2004; 31: Kone-Paut I, Shahram F, Darce-Bello M, Cantarini L, Cimaz R, Gattorno M, et al. Consensus classification criteria for paediatric Behcet s disease from a prospective observational cohort: PEDBD. Ann Rheum Dis 2015, doi: / annrheumdis Hernandez-Rodriguez J, Hoffman GS. Updating singleorgan vasculitis. Curr Opin Rheumatol 2012; 24: Baldwin C, Carette S, Pagnoux C. Linking classification and therapeutic management of vasculitides. Arthritis Res Ther 2015; 17: Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, et al. A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations.J Rheumatol 2015; 42: Annals of Paediatric Rheumatology Year 2016 Volume:5 Issue:1 1-10