American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Diagnostic and Classification Criteria for Primary Systemic Vasculitis

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Brief Title

American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Diagnostic and Classification Criteria for Primary Systemic Vasculitis

Official Title

ACR/EULAR Endorsed Study to Develop New Diagnostic and Classification Criteria for Primary Systemic Vasculitis

Brief Summary

      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.

Detailed Description

      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

Study Type


Primary Outcome

Develop new diagnostic and classification criteria for ANCA associated vasculitis and polyarteritis nodosa


Wegener's Granulomatosis

Study Arms / Comparison Groups

 WG classification
Description:  Patients with Wegener's granulomatosis. 1st half of these patients will be assigned to the development cohort and the second half to the validation cohort. Classification criteria.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

January 2011

Completion Date

December 2018

Primary Completion Date

December 2017

Eligibility Criteria

        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.




18 Years - N/A

Accepts Healthy Volunteers



Raashid A Luqmani, DM, FRCP(E), +44 1865 738106, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

University of Oxford


 American College of Rheumatology

Study Sponsor

Raashid A Luqmani, DM, FRCP(E), Principal Investigator, University of Oxford, United Kingdom

Verification Date

August 2016