American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Diagnostic and Classification Criteria for Primary Systemic Vasculitis
American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Diagnostic and Classification Criteria for Primary Systemic Vasculitis
Vasculitis is group of diseases where inflammation of blood vessels is the common feature.
 Patients typically present with fever, fatigue, weakness and muscle and joint aches. These
 symptoms are very common among many different diseases, not just vasculitis. A clustering of
 other symptoms, physical examination findings, blood tests, radiology and biopsy help make
 the diagnosis. There are currently no criteria to help doctors make a diagnosis of vasculitis
 when a patient presents with these non specific symptoms and they are reliant on previous
 experience and disease definitions. One of the aims of this project is to develop diagnostic
 criteria for the primary systemic vasculitides (granulomatosis with polyangiitis (Wegener's),
 microscopic polyangiitis, Churg Strauss syndrome, polyarteritis nodosa, giant cell arteritis,
 Takayasu arteritis). We, the investigators, will do this by studying a large group of
 patients with vasculitis and comparing them to a large group of patients that present in a
 similar way, but do not have vasculitis. By comparing the 2 groups we will create a list of
 items to differentiate between vasculitis and 'vasculitis mimics'.

 We also aim to update the current classification criteria. Classification criteria are used
 to group patients into different types of vasculitis, once a diagnosis of vasculitis has been
 made, and are useful for studying patients in clinical trials with similar or identical
 diseases. The current classification criteria (American college of Rheumatology 1990
 criteria) were developed 20 years ago, before the availability of some important diagnostic
 tests (e.g. antineutrophil cytoplasmic antibodies [ANCA]), and are now not consistent with
 some of the current disease definitions. Therefore to progress future research in vasculitis,
 it is important that the classification criteria are updated. We will recruit 260 patients
 with each of the 6 types of vasculitis and compare them with 1300 controls (patients with the
 5 other types of vasculitis), in order to determine the optimal combination of symptoms,
 signs and investigations that classify each person into the appropriate group.
The systemic vasculitides are a group of uncommon but important diseases whose prognosis has
 improved dramatically with the use of immunosuppressive therapy. However, long-term morbidity
 from recurrent disease flares, low-grade grumbling disease and/or accumulating damage from
 previous disease activity or drug therapy now characterise the long-term outlook for patients
 with vasculitis. There remains major controversy, and incompatibility between the
 ANCA-associated vasculitides: granulomatosis with polyangiitis (Wegener's), microscopic
 polyangiitis, and Churg Strauss Syndrome, as well as polyarteritis nodosa in the current
 classification criteria and disease definitions. Importantly, there are no diagnostic
 criteria for any of the primary systemic vasculitides.

 We propose to improve existing classification criteria for the primary systemic vasculitides.
 As a starting point will include the following diseases: granulomatosis with polyangiitis
 (Wegener's) (GPA), microscopic polyangiitis (MPA), Churg Strauss syndrome (CSS),
 polyarteritis nodosa (PAN), giant cell arteritis (GCA) and Takayasu arteritis (TAK).

 We propose to develop and validate classification and diagnostic criteria for primary
 systemic vasculitis using the guidelines suggested by the Classification and Response
 Criteria Subcommittee of the American College of Rheumatology Committee on Quality Measures.
 For all patients, a detailed medical history, physical examination, laboratory tests
 (including ANCA), radiology (including angiography), biopsy results, treatment, Birmingham
 Vasculitis Activity Score (BVAS)version 3, Vasculitis Damage Index (VDI), will be collected.
 The exact list of items to be recorded will be determined by the expert panel at the start of
 the study.

 Classification criteria

 We will study a minimum of 100 patients (new and existing patients) prospectively within each
 currently defined disease category (GPA, CSS, MPA, PAN, GCA, TAK) for the development of the
 classification criteria. We anticipate the need to recruit 130 patients to account for
 misdiagnosis and dropout to achieve the target of 100 with the confirmed reference diagnosis.
 This will include patients that have vasculitis which are assumed to be related to ANCA but
 do not fulfil the current definitions of any of the diseases, and patients with large vessel
 vasculitis which do not fulfil current definition for GCA or TAK. Therefore new categories of
 disease may be created as part of this process and some of the current disease categories may
 be changed to include or exclude certain patients.

 The other diseases will be the controls. The same minimum number of patients will be used to
 validate the criteria. The 1st 100 patients with a formal reference diagnosis that are
 recruited for each disease will be used for development of the classification criteria; the
 next 100 consecutive patients recruited with a confirmed reference diagnosis for each disease
 will be used to validate the criteria. Again we anticipate the need to recruit 130 patients
 to account for misdiagnosis and dropout to achieve the 100 target. The majority of cases
 included will be the same as that used for the development of the diagnostic criteria.

 In the absence of an established gold standard, we propose to develop a reference standard.
 Clinical vignettes using clustering of clinical features and investigations will be
 constructed from actual cases by the steering group. An expert panel will then be asked to
 classify each vignette. Hypothetical changes will then be made to components of each clinical
 vignette and the expert panel will be asked to re classify the case. This process will be
 repeated multiple times in an attempt to determine what key clinical feature influence the
 expert panel to change the diagnosis. Using this data driven process, a construct of
 important clinical features for each disease will be determined by the expert panel. Using
 this new construct, patients will be classified by the expert panel. This will form the
 reference standard against which the new criteria will be tested.

 Diagnostic Criteria

 We propose to develop and validate diagnostic criteria for primary systemic vasculitis. Based
 on current disease categories we will include GPA, MPA, CSS, PAN, GCA and TAK (but this may
 change depending on whether new categories are created or existing categories merged as part
 of the classification criteria component). For the development of diagnostic criteria, we
 will study a minimum of 100 patients (will require approx 130 patients to allow for dropout
 and misdiagnosis) for each disease category. Assuming 6 disease categories, the majority of
 these 780 patients will have already been identified from the classification criteria
 component of the study and will be re used for the development and validation of diagnostic
 criteria. However, for the diagnostic criteria to be clinically relevant we will only include
 patients that are seen at the time of 1st presentation, therefore not all the 780 patients
 recruited for the classification criteria section of the study will be suitable, and we will
 need to recruit additional new patients for each of the types of vasculitis being studied.

 We will use a minimum of 400 context specific controls (patients that don't have vasculitis)
 for AAV and PAN that will cover the spectrum of different disease presentations and severity.
 In addition, we will recruit a minimum of 100 context specific controls for GCA and a similar
 number for TAK. Different control populations are needed for AAV, GCA and TAK as they have
 significantly different clinical presentations. In a similar manner to cases, we will recruit
 30% more patients than the minimum required to account for misdiagnosis and drop out. The
 same minimum number of cases and controls will be needed to validate the criteria. The first
 half of the patients recruited would be used to develop the criteria, and the 2nd half to
 validate the criteria. We will allow inclusion of patients from previously studied
 prospective cohorts that meet all the appropriate inclusion / exclusion criteria and have had
 all the appropriate clinical information and mandatory investigation (to be defined later)
 recorded at time of their first presentation. This is to facilitate the recruitment of
 sufficient patients with PAN, CSS and TAK which are rare conditions.

 Statistical analysis

 We will follow the ACR recommended statistical methods for creating the classification
 criteria. Patients will have been classified into the different types of vasculitis according
 to the proposed EULAR/ACR schema by the expert panel or as a vasculitis mimic. The outcomes
 of interest are binary variables indicating whether or not a patient has been classified as
 having a particular type of vasculitis, such as GPA, MPA, etc. For each outcome,
 multivariable logistic regression modeling will be used to identify predictors of outcome
 based on the list of potential predictor variables described earlier. We will also explore
 the use of Classification And Regression Tree (CART) analysis. This is a tree-building
 technique ideally suited to the generation of clinical decision rules. Unlike conventional
 regression methods, patients are partitioned ("split") into different groups based on an
 exhaustive search of all possible predictor variables. The advantage of CART analysis over
 conventional methods is that it is non-parametric, so no assumptions are made about the
 underlying distribution of predictor variables. CART can handle many hundreds of possible
 predictor variables and can uncover complex interactions between predictors which may be
 difficult or impossible to uncover using traditional multivariate techniques that can suffer
 from model over fitting. In addition, clinicians generally do not think in terms of
 probability but rather in terms of categories, such as low versus high risk. Clinical
 decision rules generated using CART analysis are more likely to make clinical sense, and
 hence more likely to be followed in clinical practice.

 Once the best items are identified, the expert panel will decide on the best short list of
 items to be included in each criteria and also choose the most appropriate decision tree.
 This will provide the best content validity.

 The statistical methods to be used for diagnostic criteria will be very similar to that used
 for the classification criteria. The binary outcome for analysis is whether the person is a
 case or control (without vasculitis). We repeat the analyses for each of each type of
 vasculitis e.g. WG versus controls, then CSS versus controls etc
Inclusion Criteria for Classification criteria:

 1. Adult patients aged >18 years. There is no upper age limit.

 2. Ability to give informed consent. If the patient is unable to give informed consent as
 a result of death or physical incapacity, then informed assent from next of kin.

 3. Presumed diagnosis of a primary systemic vasculitis.

 Exclusion criteria for classification criteria:

 1. Patients < 18 years of age.

 2. Inability to provide informed consent.

 3. Hepatitis B or C

 4. Co-morbidities that explain the clinical symptoms and signs on which the diagnosis of
 vasculitis is made. E.g. infection, tumour, other inflammatory condition, etc.

 Inclusion criteria for diagnostic criteria:

 1. Adult patients aged >18 years. There is no upper age limit.

 2. Ability to give informed consent. If the patient is unable to give informed consent as
 a result of death or physical incapacity, then informed assent from next of kin.

 3. Suspected diagnosis of a primary systemic vasculitis

 Inclusion criteria for controls group for diagnostic criteria:

 1. Adult patients aged >18 years. There is no upper age limit.

 2. Ability to give informed consent. If the patient is unable to give informed consent as
 a result of death or physical incapacity, then informed assent from next of kin.

 3. Patients presenting to secondary care with one of the following clinical
 presentations: I.Multi-system disease. Presentation of disease with at least 2 organs
 involved. II.Pulmonary-renal syndrome. Defined as haemoptysis / pulmonary haemorrhage
 with acute renal impairment. III.Acute renal failure IV.Acute respiratory distress.
 V.Chronic upper airways symptoms and signs. VI.Inflammatory polyarthritis. VII.Fever
 of unknown origin. VIII.Acute or chronic abdominal pain IX.Hypertension. X.Referred to
 secondary care with suspicion of vasculitis but confirmed not to have vasculitis.
 XII.New onset headache. XIII.Jaw or tongue pain. XIV.Sudden visual loss. XV.Limb
 claudication. XVI.Aortic aneurysm >5cm.

 Exclusion Criteria for diagnostic criteria:

 1. Patients under the age of 18

 2. Patient or next of kin unable or unwilling to provide informed consent or assent.