Recent developments in the classification and assessment of vasculitis

Best Practice & Research Clinical Rheumatology 23 (2009) 429–443

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Recent developments in the classification and assessment of vasculitis Richard A. Watts, DM, FRCP, Clinical Senior Lecturer a, *, David G.I. Scott, MD, FRCP, Consultant Rheumatologist b a b

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK Department of Rheumatology, Norfolk and Norwich University Hospital NHS Trust, Norwich, UK

Keywords: vasculitis classification criteria diagnostic criteria assessment disease activity damage index

The systemic vasculitides are a group of multisystem diseases characterized by inflammation of blood vessels. The aetiopathogenesis is unknown, and therefore nomenclature and classification are often descriptive and based on pathological features. Generally agreed classification schemes are vital to enable large multicentre or multinational clinical trials to be undertaken. An algorithm has recently been developed to harmonize use of the American College of Rheumatology (ACR) 1990 criteria and the Chapel Hill Consensus Conference definitions. Despite this, a revision of the classification criteria is still needed, and diagnostic criteria need to be developed ab initio. The very complexity of the diseases makes accurate objective assessment critical, especially for the conduct of clinical trials. Several standardized assessment tools for both disease activity and damage have been developed over the past two decades and are now widely used in both clinical trials and routine practice. A second generation of tools is now under development. Ó 2008 Elsevier Ltd. All rights reserved.

The term vasculitis means inflammation of blood vessels, the blood vessel being the primary site of inflammation. The pathological consequence of such inflammation is destruction of the vessel wall, seen histologically as fibrinoid necrosis, hence the term ‘necrotizing vasculitis’. Vasculitis may be localized to a single organ or vascular bed and may be clinically insignificant, but more commonly it is generalized. Muscular arteries may develop focal or segmental lesions and these may be

* Corresponding author. E-mail address: [email protected] (R.A. Watts). 1521-6942/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2008.12.004

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life-threatening. Focal lesions, affecting part of the vessel wall, may lead to aneurysm formation and possible vessel rupture; segmental lesions (affecting the whole circumference) are more common and lead to stenosis or occlusion with distal infarction. The classification of vasculitis has been an area of controversy for many years, with specific classification criteria only relatively recently introduced. Disease assessment using objective tools is also an area of active development; the initial tools were devised two decades ago and are now undergoing further revision and refinement.

Classification of vasculitis Historical background Kussmaul and Maier [1] are generally accepted as having provided the first description of ‘periarteritis nodosa’ when they described a patient with a systemic illness characterized by numerous nodules along the course of small muscular arteries. Earlier descriptions suggest that the formal recording of this condition is at least 200 years old (reviewed by Matteson [2]. Zeek [3] reviewed the literature relating to vasculitis and periarteritis nodosa, and used the generic term ‘necrotizing angiitis’ to indicate the specific damage to the blood vessel wall rather than the presence of inflammation alone. She classified the vasculitides into five distinct entities: (1) hypersensitivity angiitis; (2) allergic granulomatous angiitis; (3) rheumatic arteritis; (4) periarteritis nodosa; and (5) temporal arteritis. Most modern classifications are based on Zeek’s work, which essentially combined histological changes and clinical features. Notable omissions from Zeek’s classification were Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and Takayasu arteritis (TA). Microscopic polyangiitis had been described by Davson [4] in 1948, but was not generally recognized until the 1990s. Wegener’s granulomatosis and TA were not fully recognized in the English literature until after 1953. The most widely accepted classification system, based on Zeek, reflects dominant vessel size and association with antineutrophil cytoplasmic antibodies (ANCAs) (Table 1). This classification system also broadly reflects the therapeutic approaches that are applied to the different groups (Table 2). The medium- and small-vessel groups respond well to immunosuppression with cyclophosphamide and corticosteroids, whereas the large-vessel group requires moderate- to high-dose steroids, and the small-vessel group only sometimes requires low-dose corticosteroids. Also the small–medium-vessel group includes those most likely to develop glomerulonephritis and renal failure, is associated with

Table 1 Classification of systemic vasculitis. Dominant vessel involved

Primary

Secondary

Large arteries

Giant cell arteritis Takayasu arteritis Classical PAN Kawasaki disease Wegener’s granulomatosisa Churg–Strauss syndromea Microscopic polyangiitisa

Aortitis associated with RA Infection (e.g. syphilis, tuberculosis) HBV-associated PAN

Medium arteries Small vessels and medium arteries

Small vessels (leukocytoclastic)

Henoch–Scho¨nlein purpura Cutaneous leucocytoclastic Angitis Mixed essential cryoglobulinaemia

Vasculitis secondary to RA, SLE, Sjo¨gren’s syndrome Drugsb Infection (e.g. HIV) Drugsc Infection HCV-induced cryoglobulinaemia

RA, rheumatoid arthritis; PAN, polyarteritis nodosa; HBV, hepatitis B virus; SLE, systemic lupus erythematosus; HCV, hepatitis C virus. a Diseases most commonly associated with antineutrophil cytoplasmic antibody (ANCA) (anti-myeloperoxidase and antiproteinase 3 antibodies) with a significant risk of renal involvement and which are most responsive to immunosuppression with cyclophosphamide. b Most commonly propylthiouracil or hydralazine which may induce an ANCA- associated vasculitis typically associated with myeloperoxidase-specific ANCA (MPO-ANCA). c For example, sulphonamides, penicillins, thiazide diuretics and many others.

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Table 2 Relationship between vessel size and response to induction treatment. Dominant vessel

Corticosteroids alone

Cyclophosphamide and corticosteroidsa

Other treatments

Large arteries Medium arteries Small vessels and medium arteries Small vessels

þþþ þ þ þ

 þþ þþþ þ/

þ þþb þ þþb

a Increasingly other induction are agents are being used: e.g. methotrexate in non-life-threatening antineutrophil-cytoplasmic-antibody- (ANCA-)associated vasculitis. b Includes plasmapheresis, antiviral therapy for hepatitis-B-associated polyarteritis nodosa (PAN) and hepatitis-C-virus(HCV-)associated cryoglobulinaemia, and intravenous immunoglobulin (IVIg) for Kawasaki disease.

ANCAs, and has different pathogenesis to the small-vessel group, which is often associated with immune complexes. This has led to the emergence of the concept of ANCA-associated vasculitis (AAV) to reflect the notion that WG, MPA and Churg–Strauss syndrome (CSS) share many features in common and are often included together in clinical trials. ACR (1990) criteria The American College of Rheumatology (ACR) in 1990 proposed criteria for the classification of seven different vasculitides – giant cell arteritis (GCA), Takayasu arteritis (TA), Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS), polyarteritis nodosa (PAN), Henoch–Scho¨nlein purpura (HSP), hypersensitivity vasculitis (HSV) – with sensitivities of 71.0–95.3% and specificities of 78.7–99.7% [5–14]. The most sensitive and specific criteria were found in CSS, GCA and TA; HSV (leucocytoclastic) was the least well-defined condition. This development was important because it allowed epidemiological and clinical studies to be performed using established criteria [9]. The ACR criteria have a number of drawbacks. The criteria were developed before the widespread introduction of ANCA testing which now plays a key role in the diagnosis of many patients with WG, MPA, CSS (and also in PAN, because of the absence of ANCAs). In some circumstances ANCAs may be used in place of tissue biopsy. They do not include MPA, which was a term not in common use during the 1980s. The criteria were established by comparing the clinical features of patients with established vasculitis for those features which were different between the different types of vasculitis. They were not established in an unselected group prior to the diagnosis of vasculitis or with other systemic diseases such as systemic lupus erythematosus or other connective tissue diseases. The reliability of these criteria when used in patients in whom vasculitis is suspected but not yet diagnosed is poor [15]. However, it is important to stress that they were designed as classification criteria and not diagnostic criteria. Chapel Hill consensus definitions In 1994 the Chapel Hill Consensus conference (CHCC) produced definitions for vasculitis [16]. They included MPA, but were not intended either as classification or diagnostic criteria. They recognized that histological data would not be available for all patients, especially when the clinical condition of the patient might preclude obtaining appropriate biopsies or the sample might not be representative and miss salient histological features. The concept of surrogate markers of vasculitis was therefore introduced, but a list of markers was not provided. In addition, the importance of ANCA in diagnosis was recognized. However, neither surrogate markers nor ANCA were included in the definitions. Developments following Chapel Hill There have been two major attempts at adapting the CHCC definitions for use as classification and diagnostic criteria [17,18]. Hagen et al used the CHCC definitions in a study assessing the

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standardization of ANCA assays [17]. The same methods have been used in the EUVAS clinical trials [19]. This approach accepted that histology was not available for all patients and used surrogate markers for vasculitis. There was no attempt to validate this scheme, and the use of ANCA was specifically excluded. Sorensen et al evaluated the use of the CHCC definitions with surrogate markers as diagnostic criteria in AAV [18]. They found the definitions supplemented with surrogate markers to be unhelpful in diagnosis, and proposed new diagnostic criteria for the diagnosis of WG and MPA. Application of the Sorensen diagnostic criteria to a cohort of patients with AAV collected via a prospective vasculitis register also suggested that the criteria for MPA were not helpful for classification purposes; 50 of 55 patients who fulfilled the ACR classification for WG also could be classified as MPA [20]. The absence of MPA from the ACR criteria has led to attempts to use both these criteria and the CHCC definitions in parallel. Unfortunately this results in an unacceptable degree of overlap between MPA and PAN. We have applied the ACR criteria and CHCC definitions in parallel to a prospective cohort of 99 patients from our well-defined population in Norfolk, UK. In addition, we also applied a clinical classification published by Lanham et al in 1984 for CSS, because in our experience some patients with a clinical diagnosis of CSS cannot be classified by either CHCC or ACR criteria [21,22]. Application of the ACR criteria alone resulted in significant overlap between diagnoses (Fig. 1a). Applying the CHCC definitions without surrogate markers or ANCA resulted in no overlapping diagnoses but 37 patients could not be classified (Fig. 1b) [23]. Development of the EMEA algorithm for classification AAV and PAN In order to address the issues of lack of compatibility between the ACR (1990) criteria and the CHCC definitions for AAV and PAN, a series of consensus meetings were convened by the European Medicines Agency (EMEA) with the aim of developing a consensus method of applying the two systems [24]. By consensus it was agreed to apply the classification criteria for individual diagnoses in a stepwise manner and to develop an algorithm for the classification of AAV and PAN (Fig. 2). It was agreed to give priority to the ACR criteria for CSS and WG and apply these first because they have been validated and were specifically designed as classification criteria [11,13]. The ACR criteria for CSS have the highest specificity and are applied first (Fig. 2, step 1). A few patients with CSS may only be classified using the Lanham criteria, and therefore this is included in the

WG (55)

CSS (16)

20

0

8

WG

CSS

12

4

MPA

cPAN

46

0

1 34

7

PAN (60) 18

11 Unclassified 37 Unclassified

a

b

Fig. 1. Application of (a) the American College of Rheumatology (ACR) 1990 criteria; and (b) the Chapel Hill Consensus conference (CHCC) definitions for Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS), microscopic polyangiitis (MPA), and polyarteritis nodosa (PAN) to a cohort of 99 patients. From Lane et al (2005, QJM 98: 97–111) with permission.

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Cases with a clinical diagnosis of ANCAassociated vasculitis or PAN

Fulfils ACR or Lanham criteria for CSS? Yes

1

No

Fulfils ACR criteria for WG

CSS Yes

2a

No Histology compatible with CHCC WG

Yes

2b

No WG Yes Histology compatible with CHCC MPA +WG surrogate markers

Yes

2c

No

No Histology, WG surrogate markers present AND +ve PR3-ANCA or MPO-ANCA

2d

No

Histology compatible with small vessel vasculitis. No WG surrogate markers. Yes

MPA Yes

3a

No No Histology. No WG surrogate markers. Surrogate markers for renal vasculitis AND +ve PR3-ANCA or MPO-ANCA *includes renal limited vasculitis

3b

No cPAN

Yes

Histology compatible with CHCC cPAN or Angiographic Features typical of cPAN

4

No Unclassified Fig. 2. Algorithm for the classification of vasculitides. From Watts et al (2007, Ann Rheum Dis 66:222–7) with permission.

first stage [22]. It was recognized by the group that some patients clinically diagnosed as ‘other vasculitides’ might be classified as CSS, but the number of patients affected would be small. The second stage is to classify WG (Fig. 2, steps 2a–d). The ACR criteria are applied first as they have been validated with high specificity and sensitivity [5]. Then the CHCC definitions are applied using the strict histological definitions only, not surrogate markers or ANCA. For a classification of CHCC WG there has to be evidence of granulomatous change on biopsy. Small-vessel vasculitis alone

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Table 3 Surrogate markers for vasculitis. 1. Surrogate markers for WG (granulomatous disease) refer to symptoms suggestive of granulomatous disease affecting the upper and lower respiratory tract (in all cases other causes must be excluded): (a) Lower airways  X-ray evidence of fixed pulmonary infiltrates, nodules or cavitations present for >1 month.  Bronchial stenosis (b) Upper airways  bloody nasal discharge and crusting for >1 month, or nasal ulceration  chronic sinusitis, otitis media or mastoiditis for >3 months  retro-orbital mass or inflammation (pseudotumour)  subglottic stenosis  saddle-nose deformity/destructive sinonasal disease Only one surrogate marker is necessary to support a diagnosis of WG. 2. Surrogate markers for renal vasculitis (glomerulonephritis) are either:  haematuria associated with red cell casts or >10% dysmorphic erythrocytes,  or 2þ haematuria AND 2þ proteinuria on urinalysis From Watts et al (2007, Ann Rheum Dis 66:222–7) with permission.

is classified as CHCC MPA. The next stage is to distinguish between WG and MPA. Surrogate markers for WG were defined by the group (Table 3). A patient is classified as WG if there are surrogate markers for WG and histology compatible with MPA. If histology is not available but surrogate markers of WG are present and ANCA (either c/pANCA or PR3/MPO-ANCA) is detected, then the patient is classified as WG. The third and fourth stages are to distinguish between MPA and classic PAN using the CHCC definitions for MPA and cPAN and surrogate markers for renal vasculitis and ANCA (Figure 2, steps 3 and 4) (Table 3). The presence of histologically proven small-vessel vasculitis or glomerulonephritis differentiates MPA from cPAN. ANCA was felt by the group to be a feature of MPA and not cPAN [25]. The ACR criteria for PAN are not included in the algorithm because they have relatively poor specificity [12], and many patients classified as ACR PAN also fulfil other classification criteria (Fig. 1). Prior to entering the algorithm a patient must fulfil the entry criteria for a clinical diagnosis of AAV or PAN (Table 1), the key feature being that the patient must have a clinical condition compatible with AAV or PAN, and that no other condition is more likely. The algorithm is applied using clinical features that have EVER been present during the course of the disease, not only at diagnosis. The patient should have been followed for at least 3 months where possible. Patients who do not survive for 3 months or are lost to follow-up can be classified provided they are considered to have a clinical diagnosis of AAV or PAN. The following provisos were made for the application of the classification scheme: (1) ACR criteria must be applied strictly, i.e. peripheral-blood eosinophilia must be >10% (or >1.5  109/L) for CSS, and fixed infiltrates must be present on chest x-ray for >1 month for WG [3]; (2) CHCC definitions refer to the histological definitions only and should not include the use of ANCA or surrogate markers [16]; and (3) surrogate markers for WG (granulomatous disease) refer to symptoms suggestive of granulomatous disease affecting the upper and lower respiratory tract (in all cases other causes must be excluded) (Table 3). The algorithm was subjected to a three-stage validation process: 1. The algorithm was initially tested on 99 patients with AAV/PAN from a single centre (Norwich, UK). The patients were part of a cohort of AAV/PAN from a well-defined population and have been described elsewhere [23]. This demonstrated that the algorithm achieved the aim of classifying all patients with no unclassified patients. 2. Face validity was confirmed by each member of the group using 20 of their own cases with a known clinical diagnosis of AAV or PAN. 3. The algorithm was then tested using paper cases to demonstrate inter-observer reliability. The overall percentage agreement between the participants and the standard paper case diagnosis was 91.5%. The unweighted kappa statistic was 0.885 (95% CI: 0.836–0.935), suggesting that the algorithm is reproducible between observers.

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It was therefore concluded that the algorithm was a reliable method of applying the ACR (1990) criteria and CHCC definitions in a consistent manner for epidemiological studies. More recently the algorithm has been tested in a large cohort (550) of Chinese patients with primary systemic vasculitis [26]; 493 were ANCA-positive. The ratio of patients with WG and MPA is different in China and Japan from that in Europe. In China and Japan MPA is more common than WG [26,27]. In most of Europe the ratio is the reverse. The algorithm successfully achieved the aim of classifying the patients into a single category with only 20 (3.6%) patients unclassified. Using the algorithm, no patients were classified as PAN compared to four using the CHCC definition; this is in accordance with our experience. Patients with a classification of MPA by CHCC (363) divided into WG (37), MPA (324) and CSS (2). The number of unclassified patients was reduced from 56 to 20. The algorithm works successfully in a region where the spectrum of disease is different from that in Europe. It is important to recognize that the algorithm was developed and validated for epidemiological studies rather than for clinical trials. Its use in the latter setting requires validation. PAN versus MPA One of the main problems with the ACR criteria is that they do not include MPA, and consequently the ability to distinguish between PAN and MPA is poor. Henegar and colleagues recently conducted a detailed study of 949 patients with systemic vasculitis in the French Vasculitis Study Group database with the aim of developing better criteria for PAN [28]. The study included 262 patients with PAN (108 HBV-associated PAN), 256 WG, 207 MPA, 150 CSS, 18 cryoglobulinaemic vasculitis, and 56 other types of vasculitis. They introduced the concept of negative predictive parameters in addition to positive ones. Of the original ten ACR criteria they maintained only three (hepatitis B virus antigen, arteriographic abnormalities, and polyneuropathy). They introduced five negative criteria, including negative indirect immunofluorescence detection of ANCA (see Table 4). These criteria had 70.6% sensitivity against all vasculitis controls with 92.3% specificity. When compared against MPA there was 89.7% sensitivity and 83.1% specificity. The discriminant ability of this set of items performs better than the ACR (1990) criteria in all settings. These criteria remain to be validated as diagnostic criteria. Large-vessel vasculitis The ACR (1990) criteria and CHCC definitions for large-vessel vasculitis are generally accepted. They both have a high specificity and sensitivity. The main discrepancy is the age cut-off criterion. In the ACR criteria the discriminating age for TA is 40 years, whereas in the CHCC it is 50 years. It is considered that this is restrictive, and there is support for the notion that the age criterion for both GCA and TA should be removed.

Table 4 The French Vasculitis Study Group minimal set of low-redundant polyarteritis-nodosa- (PAN-) predictive criteria. Criterion

PAN association

Definition

1. HBV infection

Positive

2. 3. 4. 5. 6.

Negative Negative Negative Negative Negative

Markers reflecting active HBV replication, such as the presence of HBeAg in serum and/or HBV DNA at >105 copies/mL Presence of ANCA in serum, by indirect immunofluorescence Previous history of asthma Signs of maxillary sinusitis or otitis media Detection of cryoglobulins in serum Signs of glomerulopathy, such as proteinuria and/or haematuria with or without renal insufficiency, not due to urinary tract infection, urolithiasis, or haematological or other non-glomerular causes Arteriogram showing aneurysms or occlusions of the visceral arteries, not due to arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes Development of polyneuropathy, multiple mononeuropathies or polyneuropathy

ANCA positivity Asthma ENT signs Cryoglobulin positivity Glomerulopathy

7. Arteriographic abnormalities 8. Mono/polyneuropathy

Positive Positive

HBV, hepatitis B virus; ANCA, antineutrophil cytoplasmic antibody; ENT, ear nose and throat. From Henegar et al (2008, Arthritis Rheum 58:1528–38) with permission.

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EULAR/PReS criteria for childhood vasculitis A EULAR/Paediatric Rheumatology European Society (EULAR/PReS) working group has recently developed classification criteria for childhood vasculitis using a Delphi technique [29]. There was agreement to classify childhood vasculitis according vessel size, with small-vessel diseases subdivided into granulomatous and non-granulomatous. Classification criteria were developed for HSP, Kawasaki disease (KD), childhood PAN, WG and TA. These criteria have not yet been validated. The existing ACR criteria for HSP were modified to remove the age criterion, and the presence of IgA deposits on histopathology was highlighted (Table 5). The presence of palpable purpura was made mandatory, as this has been shown to improve the specificity of the criteria in a study of patients with PAN. For KD the Japanese and American criteria [30,31], which are different, were modified to include perineal desquamation, and the importance of coronary artery involvement was highlighted (Table 6). The precise number of criteria remains to be determined in the validation. The existing ACR criteria for PAN were felt by consensus to be unsuitable for the classification of childhood PAN, in particular because streptococcal infections play an important role in children. Potential criteria were therefore evaluated using the PReS registry of 110 patients with PAN to determine the most sensitive and specific criteria (Table 7) [32]. It is worth noting that hepatitis B infection is not a criterion (as this is rarely a feature in children with improved vaccination protocols) but is indicative of a vasculitis associated with infection. Cutaneous polyarteritis nodosa was felt in children to be a distinct condition from the systemic illness of childhood PAN. Classification criteria for cutaneous PAN were not developed, but the features were considered to be: 1. rash characterized by the presence of subcutaneous nodular, painful, non-purpuric lesions with or without livedo reticularis, with no systemic involvement apart from myalgia, arthralgia and nonerosive arthritis; 2. skin biopsy showing necrotizing non-granulomatous vasculitis; 3. negative ANCA; 4. serological or microbiological evidence of streptococcal infection. The ACR criteria for WG were modified to include two new criteria: (1) the presence of subglottic, tracheal or endobronchial stenosis; and (2) the presence of high levels of PR3-ANCA or positive cANCA by indirect immunofluorescence (Table 8). Microscopic polyangiitis was not classified by the ACR; the EULAR/PReS group adopted the CHCC definition, but added an association with MPO-ANCA to the definition. The group did not develop new classification criteria. The EULAR/PReS modified the ACR criteria for TA, by making the presence of angiographic abnormalities mandatory (Table 9). They did not define the radiological technique to be employed. Hypertension (age-appropriate) was added, as this may be the sole presenting feature of TA in childhood. The age criterion was removed. Current research agenda An international expert working group has been convened under the sponsorship of both EULAR and ACR to consider the development of revised classification criteria and new diagnostic criteria for adult vasculitis. This group is at present reviewing the current relevance of the criteria with a view to Table 5 European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PReS) classification criteria for childhood Henoch–Scho¨nlein purpura. Palpable purpura (mandatory) in the presence of at least one of the following four features:  diffuse abdominal pain  any biopsy showing predominant IgA deposition  arthritis (any joint) or arthralgia  renal involvement (any haematuria/proteinuria) From Ozen et al (2006, Ann Rheum Dis 65:936–41) with permission.

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Table 6 European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PReS) classification criteria for Kawasaki disease. Fever persisting for at least 5 days (mandatory criterion) plus four of the following five features:  changes in peripheral extremities or perineal area  polymorphous exanthema  bilateral conjunctival injection  changes of lips and oral cavity: injection of oral and pharyngeal mucosa  cervical lymphadenopathy In the presence of coronary artery involvement (detected on echocardiography) and fever, fewer than four of the remaining five criteria are sufficient. From Ozen et al (2006, Ann Rheum Dis 65:936–41) with permission.

producing modified classification criteria, which will then be submitted to a formal validation exercise. Paediatricians have been included in this working group to ensure minimal conflict between the EULA/ PReS childhood criteria and the modified adult criteria. New criteria for diagnosis will also be developed. Assessment of vasculitis The assessment of patients with systemic vasculitis has become much more objective over the past 20 years with the development of several scoring systems. All of these were originally developed for use in clinical trials, but are increasingly used in routine clinical practice. The systemic vasculitides were until relatively recently associated with significant mortality and morbidity. However, modern treatment protocols have converted these diseases into chronic relapsing remitting conditions. Complete assessment of the patient with vasculitis therefore needs to cover the three domains: (1) disease activity; (2) damage due to previous disease activity; and (3) functional assessment. Disease activity The patient presenting with a new diagnosis of vasculitis or a relapse of previously well-controlled disease requires a comprehensive assessment of organ involvement in order to tailor therapy precisely to their needs. There are now several instruments which permit detailed assessment of disease activity: for example the Birmingham Vasculitis Activity Score (BVAS) [33,34]. The BVAS is a clinical index based on nine systems, including 66 clinical features. Each disease manifestation is only scored if it is attributable to active vasculitis. The BVAS was validated and has

Table 7 European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PReS) classification criteria for childhood polyarteritis nodosa. A systemic illness characterized by the presence of either a biopsy showing small and mid-sized artery necrotizing vasculitis OR angiographic abnormalitiesa (aneurysms or occlusions) (mandatory criteria), plus at least two of the following:  skin involvement (livedo reticularis, tender subcutaneous nodules, other vasculitic lesions)  myalgia or muscle tenderness  systemic hypertension, relative to childhood normative data  mononeuropathy or polyneuropathy  abnormal urine analysis and/or impaired renal functionb  testicular pain or tenderness  signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or central nervous system) From Ozen et al (2006, Ann Rheum Dis 65:936–41) with permission. a Should include conventional angiography if magnetic resonance angiography is negative. b Glomerular filtration rate of <50% normal for age.

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Table 8 European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PReS) classification criteria for childhood Wegener’s granulomatosis. Three of the following should be present:  abnormal urine analysisa  granulomatous inflammation on biopsyb  nasal sinus inflammation  subglottic, tracheal, or endobronchial stenosis  abnormal chest x-ray or CT  PR3-ANCA or C-ANCA by indirect immunofluorescence From Ozen et al (2006, Ann Rheum Dis 65:936–41) with permission. a Haematuria and/or significant proteinuria. b If a renal biopsy is done it characteristically shows necrotizing pauci-immune glomerulonephritis.

been widely used in clinical trials [35]. However, the BVAS has undergone modification in the years since it was first developed, and a revised version, BVAS 2003, is currently being validated (Mukhtar, personal communication) (Table 10). Four features that occur only rarely have been removed, and seven new items describing assessment after a specialist opinion (e.g. by an otorhinolaryngologist) or investigations added. Each item is given an arbitrary score dependent on its perceived severity: e.g. oral ulcers score 2, whereas nasal crusting scores 6. The items are grouped into nine systems, which are again weighted by allocating a maximum score: e.g. the maximum renal score is 12, but cutaneous involvement can only score a maximum of 6. The original BVAS was developed primarily as a generic instrument for use in the small/mediumvessel vasculitides. A need has therefore been felt for more disease-specific instruments, particularly where the generic instrument does not capture the full spectrum of disease activity. The disease extent index (DEI) for WG [36] and the Birmingham Vasculitis Activity Score for WG (BVAS/WG) [37] have both been developed specifically for use in WG. The rationale behind these two developments was that the DEI captures long-term outcomes and the full manifestations such as granulomatous disease better than the BVAS, whilst the BVAS/WG was developed for a short-term trial of etanercept in WG in the USA. The BVAS/WG was developed to overcome some of the limitations of the original BVAS when used for WG. The aim of the revision was threefold: (1) to remove redundant items; (2) to increase the ability of the instrument to capture disease manifestations specific to WG; and (3) to streamline the instrument for use in clinical trials [37]. Thirty-eight items were removed from the original BVAS, nine items were revised, and seven new items were added. The items were empirically weighted by expert opinion given a weighting of either 1 (minor item) or 3 (major item). The BVAS/WG was validated against the physician’s global assessment and shown to correlate well (r ¼ 0.87 95% CI 0.73–0.87). There was good inter-observer agreement, and no observer effect was found. The selection and weighting of items has recently been explored in the dataset obtained from the Wegener’s Granulomatosis Etanercept Trial [38]. This analysis has suggested some further modification to the BVAS/ WG, in particular the addition of new items reflecting weight loss and fatigue, which were not previously separately included. The BVAS in either form is the most widely used scoring system used for medium/small-vessel diseases.

Table 9 European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PReS) classification criteria for childhood Takayasu arteritis. Angiographic abnormalities (conventional, CT, or MR) of the aorta or its main branches (mandatory criterion) plus at least one of the following four features:  decreased peripheral artery pulses and/or claudication of extremities  blood pressure difference >10 mmHg  bruits over aorta and/or its major branches  hypertension (related to childhood normative data) From Ozen et al (2006, Ann Rheum Dis 65:936–41) with permission.

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Table 10 Birmingham Vasculitis Activity Score 2003. Vascular Activity Score 2003 B Tick box only if abnormality represents active disease (use the Vasculitis Damage Index, VDI to score items of damage). If there are no abnormalities in a system, please tick the ‘None’ box

None 1. General Myalgia Arthralgia or arthritis Fever 38.0  C Weight loss 2 kg

B

2. Cutaneous Infarct Purpura Ulcer Gangrene Other skin vasculitis

B

3. Mucous membranes/eyes Mouth ulcers/granulomata Genital ulcers Adnexal inflammation Significant proptosis Red eye (Epi)scleritis Red eye conjunctivitis/blepharitis/keratitis Blurred vision Sudden visual loss Uveitis Retinal vasculitis/retinal vessel Thrombosis/retinal exudates/ Retinal haemorrhages

B

4. ENT Bloody nasal discharge/nasal Crusts/ulcers and/or granulomata Paranasal sinus involvement Subglottic stenosis Conductive hearing loss Sensorineural hearing loss

B

5. Chest Wheeze Nodules or cavities Pleural effusion/pleurisy Infiltrate Endobronchial involvement Massive haemoptysis/alveolar haemorrhage Respiratory failure

B

6. Cardiovascular Loss of pulses Valvular heart disease Pericarditis Ischaemic cardiac pain Cardiomyopathy Congestive cardiac failure

B

7. Abdominal Peritonitis Bloody diarrhoea Ischaemic abdominal pain

B

If all the abnormalities recorded represent smouldering/low grade/grumbling disease, and there are no new/worse features, please remember to tick the box at the bottom right corner

B

Active disease B B B B

B B B B B

B B B B B B B B B

B

B B B B B

B B B B B B B

B B B B B B

B B B

(continued on next page)

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Table 10 (continued).

Vascular Activity Score 2003 B Tick box only if abnormality represents active disease (use the Vasculitis Damage Index, VDI to score items of damage). If there are no abnormalities in a system, please tick the ‘None’ box

If all the abnormalities recorded represent smouldering/low grade/grumbling disease, and there are no new/worse features, please remember to tick the box at the bottom right corner

B

None 8. Renal Hypertension Proteinuria >1þ Haematuria 10 bc/hpf Creatinine 125–249 mmol/L Creatinine 250–499 mmol/L Creatinine 500 mmol/L Rise in creatinine >30% or Creatinine clearance fall >25%

B

9. Nervous system Headache Meningitis Organic confusion Seizures (not hypertensive) Stroke Cord lesion Cranial nerve palsy Sensory peripheral neuropathy Motor mononeuritis multiplex

B

10. Other

B

Active disease B B B B B B

B

B B B B B B B B B

B B B

Persistent disease only: Tick here if all the above abnormalities are due to low-grade grumbling disease and not due to new/ worse disease , From Nataraja et al (2007, Best Pract Res Clin Rheumatol 21:713–32) [46] with permission.

The DEI scores the number of organ systems involved, but unlike the BVAS is unweighted, and it correlates with the original BVAS [36]. A recent comparison between the BVAS, BVAS/WG, BVAS 2003 and DEI has shown good correlation [39]. The suggestion has been made that the individual weighting may not be very important, and the OMERACT group is investigating this possibility. The five-factor score (FFS) was designed as a prognostic tool and not for serial assessment of disease [40]. It is very simple to use and provides reliable prognostic information. A key component of assessment, especially for clinical trials, is the definition of active disease, remission and relapse. The initial versions of the BVAS and DEI did define remission. There is, however, no clear consensus regarding disease remission [39]. The OMERACT group has proposed operational definitions for three disease states: high disease activity, low disease activity and remission. The three states may be qualified by the two conditions ‘on treatment’ or ‘off treatment’ [39]. These definitions are currently being evaluated using clinical datasets from several recent trials. Takayasu arteritis is a very different type of vasculitis involving predominately large vessels, with a very different spectrum of disease as compared to medium-vessel vasculitis, and so is not well covered in the BVAS system. The Indian Takayasu Activity Score (ITAS) is being developed by an Indian group [41]. The ITAS has been validated against the physician’s global assessment and shown to perform well. Damage indices The vasculitides are chronic diseases and as such patients accumulate damage to organs either as a result of disease activity or its treatment. The vasculitis damage index (VDI) is the only

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validated measure of accumulated damage [42]. It is based on a score derived from individual items from disease onset, and comprises 64 items (grouped into 11 organ-based systems). The items were originally selected by consensus amongst experienced physicians. Damage was defined by three key characteristics: irreversibility, presence for more than 3 months, and attribution of the lesion to vasculitis or its therapy. Each item was not weighted and therefore all contribute equally to the score. The VDI has been use to demonstrate that irreversible damage occurs early in the disease course and has a significant effect on later morbidity and mortality [43]. Multiorgan multisystem involvement within in 2 years is associated with an increased risk of death. The VDI was designed as a generic tool. More recently a damage tool specifically for AAV has begun to be developed: the ANCA-associated Vasculitis Index of Damage (AVID) [44]. Simultaneously with the development of AVID, there have been preliminary attempts to re-evaluate the performance of the VDI. These two projects have now been merged into a single effort to develop and validate a new tool: Combined Damage Assessment (CDA) [44]. The development will be data-driven using the clinical information gathered during various recent European and US trials. A disease-specific damage index has been developed for use in Takayasu arteritis (DEI-TAK). Again this records cumulative organ damage attributable to either the disease or its treatment [41]. Validation is currently under way. The third component of disease assessment is the patient’s assessment of their disease. Generic instruments such as the Short Form 36 (SF-36) have been shown to perform well in vasculitis [45]. However, disease-specific instruments are required. Current research agenda The major thrust of research in disease assessment is the development of a new generation of tools. Disease-specific assessment tools for both activity and damage are needed, but they should nest together so that they share common elements and underlying principles. The new tools will need extensive validation. Summary Many of the systemic vasculitides are of unknown causation, and therefore the current classification tools are based on clinical features and pathology. The validated ACR criteria predate the introduction of ANCA testing and the widespread recognition of MPA as a specific entity. The CHCC recognized MPA but did not incorporate ANCA. Use of the two systems results in conflicting classification, which has been partially resolved by the development of the EMEA algorithm which incorporates both systems. However, a major revision is needed, and this is currently under way. It should be stressed that the classification criteria should not be used as diagnostic criteria; such criteria will need to be developed separately. The complexity of the diseases requires accurate assessment and the existing tools require revision and updating. This process is under way. The most widely used is the BVAS and VDI, and these are suitable for routine clinical use.

Practice points  the systemic vasculitides are complex multi system diseases requiring detailed assessment  the existing classification schemes are imperfect but are widely used for clinical trials and epidemiological studies  there are NO validated diagnostic criteria, and classification criteria should not be used as diagnostic criteria  objective assessment tools should be used wherever possible to aid accurate assessment of individual patients

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Research agenda to revise the nomenclature of systemic vasculitis to revise the existing ACR criteria and CHCC definitions to develop new diagnostic criteria to revise and develop activity assessment tools which are more specific to each disease entity to develop new damage indices which are both generic and can be modified for use in each disease  to validate the new diagnostic and assessment tools     

References [1] Kussmaul AMK. Uber eine nicht bisher beschriebene eigenthumliche Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskelahmung einhergeht. Deutsche Archiv Klinische Medizin 1866;1:484–518. [2] Matteson EL. A history of early investigation in polyarteritis nodosa. Arthritis Care Res 1999;12(4):294–302. [3] Zeek PM. Periarteritis nodosa; a critical review. Am J Clin Pathol 1952;22(8):777–90. [4] Davson JBJ, Platt R. The kidney in periarteritis nodosa. Q J Med 1948;17:175–202. *[5] Fries JF, Hunder GG, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum 1990;33(8):1135–6. [6] Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33(8):1129–34. [7] Bloch DA, Michel BA, Hunder GG, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Patients and methods. Arthritis Rheum 1990;33(8):1068–73. [8] Calabrese LH, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 1990;33(8):1108–13. [9] Hunder GG, Arend WP, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990;33(8):1065–7. [10] Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33(8):1122–8. [11] Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33(8):1101–7. [12] Lightfoot Jr RW, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33(8):1088–93. [13] Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of ChurgStrauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33(8):1094–100. [14] Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of HenochSchonlein purpura. Arthritis Rheum 1990;33(8):1114–21. [15] 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(5):345–52. *[16] Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37(2):187–92. [17] Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA assay standardization. Kidney Int 1998;53(3):743–53. [18] Sorensen SF, Slot O, Tvede N, Petersen J. A prospective study of vasculitis patients collected in a five year period: evaluation of the Chapel Hill nomenclature. Ann Rheum Dis 2000;59(6):478–82. [19] Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349(1):36–44. [20] Lane SE, Watts RA, Barker TH, Scott DG. Evaluation of the Sorensen diagnostic criteria in the classification of systemic vasculitis. Rheumatology (Oxford) 2002;41(10):1138–41. [21] Reid AJ, Harrison BD, Watts RA, et al. Churg-Strauss syndrome in a district hospital. QJM 1998;91(3):219–29. [22] 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(2):65–81. [23] Lane SE, Watts RA, Shepstone L, Scott DG. Primary systemic vasculitis: clinical features and mortality. Qjm 2005;98(2): 97–111. *[24] Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis 2007;66:222–7. [25] Guillevin L, Pagnoux C, Teixera L. Polyarteritis Nodosa. Vasculitis. In: Bridges L, Ball G, editors. 2nd edn. Oxford: Oxford University Press; 2008. p. 335–53. *[26] Liu LJ, Chen M, Yu F, et al. Evaluation of a new algorithm in classification of systemic vasculitis. Rheumatology (Oxford) 2008;47(5):708–12. [27] Watts RA, Scott DG, Jayne DR, et al. Renal vasculitis in Japan and the UK – are there differences in epidemiology and clinical phenotype? Nephrol Dial Transplant 2008;23(12):3928–31.

R.A. Watts, D.G.I. Scott / Best Practice & Research Clinical Rheumatology 23 (2009) 429–443

443

*[28] Henegar C, Pagnoux C, Puechal X, et al. A paradigm of diagnostic criteria for polyarteritis nodosa: analysis of a series of 949 patients with vasculitides. Arthritis Rheum 2008;58(5):1528–38. *[29] Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 2006;65(7):936–41. [30] Committee JKDR. Diagnostic Guidelines for Kawasaki Disease. 2002 5th edn. Tokyo. [31] 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(6):1708–33. [32] Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. J Pediatr 2004; 145(4):517–22. [33] Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM 1994;87(11):671–8. [34] Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. Baillieres Clin Rheumatol 1997;11(2):423–46. *[35] Flossmann O, Bacon P, de Groot K, et al. Development of comprehensive disease assessment in systemic vasculitis. Ann Rheum Dis 2007;66(3):283–92. [36] de Groot K, Gross WL, Herlyn K, Reinhold-Keller E. Development and validation of a disease extent index for Wegener’s granulomatosis. Clin Nephrol 2001;55(1):31–8. [37] Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum 2001;44(4):912–20. *[38] Mahr AD, Neogi T, Lavalley MP, et al. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener’s granulomatosis. Arthritis Rheum 2008;59(6):884–91. *[39] Merkel PA, Seo P, Aries P, et al. Current status of outcome measures in vasculitis: focus on Wegener’s granulomatosis and microscopic polyangiitis. Report from OMERACT 7. J Rheumatol 2005;32(12):2488–95. [40] Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996;75(1):17–28. [41] Misra RD, Jayaseelan D, Sivakumar L, et al. ITAS and DEI.TAK - Scores for clinical disease activity and damage extent in Takayasu aorto-arteritis. Rheumatology (Oxford) 2008;47:ii101. [42] Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum 1997;40(2):371–80. [43] Exley AR, Carruthers DM, Luqmani RA, et al. Damage occurs early in systemic vasculitis and is an index of outcome. QJM 1997;90(6):391–9. [44] Seo P, Luqmani RA, Flossmann O, et al. The future of damage assessment in vasculitis. J Rheumatol 2007;34(6):1357–71. [45] Koutantji M, Harrold E, Lane SE, et al. Investigation of quality of life, mood, pain, disability, and disease status in primary systemic vasculitis. Arthritis Rheum 2003;49(6):826–37. *[46] Nataraja A, Mukhtyar C, Helmich B, et al. Outpatient assessment of systemic vasculitis. Best Pract Res Clin Rheumatol 2007;21:713–32.