Clinical trial NCT01066208: 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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Wegener's Granulomatosis
Microscopic Polyangiitis
Churg Strauss Syndrome
Polyarteritis Nodosa
Giant Cell Arteritis
Takayasu Arteritis
Keywords: Classification criteria
Diagnostic criteria
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: American College of Rheumatology
name: The European League Against Rheumatism (EULAR)
name: The Vasculitis foundation
First posted: 2010-02-10
Enrollment: 3588
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with primary systemic vasculitis or a mimic of these diseases seen in participating secondary or tertiary care centres in Europe, USA, Mexico, Japan, Asia, Australasia.

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

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.

Primary outcomes:
measure: Develop new diagnostic and classification criteria for ANCA associated vasculitis and polyarteritis nodosa
timeFrame: 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, LA
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Vasculitis Center, Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Internal Medicine
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Centre, Lebanon, NH
state: New Hampshire
city: New York
country: United States
facility: New York University Langone Medical Centre
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University Medical Center
state: Utah
city: San Fernando del Valle de Catamarca
country: Argentina
facility: Hospital Interzonal San Juan Bautista
state: Catamarca
city: Buenos Aires
country: Argentina
facility: Ramos Mejia Hospital, University of Buenos Aires
city: Canberra
country: Australia
facility: ANU Medical Centre
state: Australian Capital Territory
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Innsbruck
country: Austria
facility: Medical University Innsbruck
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: St Joseph's Healthcare
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital, Toronto
state: Ontario
city: Montreal
country: Canada
facility: McGill University
state: Quebec
city: Sherbrooke
country: Canada
facility: Sherbrooke University Hospital Centre
state: Quebec
city: Calgary
country: Canada
facility: University of Calgary
city: Ontario
country: Canada
facility: St Joseph's Healthcare London, Ontario
city: Beijing
country: China
facility: Peking Union Medical College Hospital, Beijing
city: Prague
country: Czech Republic
facility: General University Hospital, Prague
city: Prague
country: Czech Republic
facility: General University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Assiut
country: Egypt
facility: Assiut University, Assiut University Hospitals
city: Cairo
country: Egypt
facility: Cairo University, Kasr El Ainy Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Paris
country: France
facility: Cochin Hospital, Université Paris-descartes
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Luebeck
country: Germany
facility: University of Schleswig-Holstein
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Plochingen
country: Germany
facility: Kreiskliniken Esslingen
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Debrecen
country: Hungary
facility: University of Debrecen Medical and Health Science Center
city: Lucknow
country: India
facility: Chatrapathi Shahuji Maharaj Medical Center, Lucknow (IProcess)
state: Uttar Pradesh
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research, Chandigarh
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences, Hyderabad
city: New Delhi
country: India
facility: Medanta, Delhi
city: Vellore
country: India
facility: Christian Medical College & Hospital, Vellore
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin 4
country: Ireland
facility: St. Vincent's University Hospital, Dublin
city: Parma
country: Italy
facility: University of Parma
city: Reggio Emilia
country: Italy
facility: Santa Maria Nuova Hospital, Reggio Emilia
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
city: Kamogawa City
country: Japan
facility: Kameda Medical Centre, Kamogawa
state: Chiba prefecture
city: Tsukuba
country: Japan
facility: Tsukuba University Hospital
state: Ibaraki Prefecture
city: Miyazaki City
country: Japan
facility: Miyazaki University Hospital
state: Miyazaki Prefecture
city: Kawagoe
country: Japan
facility: Saitama Medical University
state: Saitama Prefecture
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo Prefecture
city: Chiba
country: Japan
facility: Chiba University
city: Kagawa
country: Japan
facility: Kagawa University Hospital
city: Kanagawa
country: Japan
facility: St. Marianna University Hospital
city: Kanazawa
country: Japan
facility: Kanazawa University Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Kitano Hospital
city: Saitama
country: Japan
facility: Juntendo University Koshigaya Hospital
city: Tochigi-ken
country: Japan
facility: Jichi Medical University Hospital
city: Tokyo
country: Japan
facility: University Tokyo Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Christchurch
country: New Zealand
facility: University of Otago, Christchurch
state: Canterbury
city: Auckland
country: New Zealand
facility: Auckland District Health Board
city: Auckland
country: New Zealand
facility: Waitemata District Health Board, North Shore Hospital
city: Hamilton
country: New Zealand
facility: Waikato District Health Board
city: Kristiansand
country: Norway
facility: Hospital of Southern Norway
city: Tromsø
country: Norway
facility: The University Hospital of Northern Norway, Tromsø
city: Kraków
country: Poland
facility: University of Jagiellonian
city: Almada
country: Portugal
facility: Hospital Garcia de Orta, Almada
city: Lisbon
country: Portugal
facility: Santa Maria Hospital, Lisbon
city: Porto
country: Portugal
facility: Hospital Santo Antonio, Porto
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Barcelona
country: Spain
facility: Clinic Barcelona Hospital Universitari
state: Catalonia
city: Columbo 8
country: Sri Lanka
facility: University of Colombo
city: Lund
country: Sweden
facility: Lund University
city: Stockholm
country: Sweden
facility: Karolinska Institute, Stockholm
city: Stockholm
country: Sweden
facility: Linköping University
city: Umeå
country: Sweden
facility: Umeå University
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Zurich
country: Switzerland
facility: Immunologie-Zentrum Zurich
city: Ankara
country: Turkey
facility: Hacettepe University
city: Istanbul
country: Turkey
facility: Istanbul University, Cerrahpasa Medical School
city: Istanbul
country: Turkey
facility: Marmara University Medical School
city: Istanbul
country: Turkey
facility: Fatih University Medical Faculty
city: Istanbul
country: Turkey
facility: Haydarpasa Education and Research Hospital
city: Istanbul
country: Turkey
facility: Istanbul University, Istanbul Medical School
city: Carlisle
country: United Kingdom
facility: North Cumbria University Hospitals, The Cumberland Infirmary
state: Cumbria
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock University Hospitals NHS Foundation Trust
state: Essex
city: Romford
country: United Kingdom
facility: Queen's Hospital
state: Essex
city: Westcliff-on-Sea
country: United Kingdom
facility: Southend University Hospital NHS Trust
state: Essex
city: Kirkcaldy
country: United Kingdom
facility: NHS Fife, Whyteman's Brae Hospital, Windygates
state: Fife
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow & Clyde, Gartnavel Hospital
state: Scotland
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital NHS Trust
state: Suffolk
city: Carshalton
country: United Kingdom
facility: Epsom and St Helier University Hospitals NHS Trust
state: Surrey
city: Birmingham
country: United Kingdom
facility: University of Birmingham
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Dudley
country: United Kingdom
facility: Dudley Group of Hospitals, NHS FT
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust, Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: University of Manchester, Manchester Royal Infirmary
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust (QMC)
city: Oxford
country: United Kingdom
facility: Nuffield Orthopaedic Centre
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust (The Churchill Hospital)
city: Reading
country: United Kingdom
facility: Royal Berkshire NHS Trust
city: Slough
country: United Kingdom
facility: Heatherwood & Wexham Park Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
city: York
country: United Kingdom
facility: York Hospital NHS Foundation Trust
Study officials:
affiliation: University of Oxford, United Kingdom
name: Raashid A Luqmani, DM, FRCP(E)
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Peter Merkel, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of East Anglia
name: Richard Watts, DM, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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 Sep 1;129(5):345-52. doi: 10.7326/0003-4819-129-5-199809010-00001.
citation: Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, Leavitt RY, Lie JT, Lightfoot RW Jr, Masi AT, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum. 1990 Aug;33(8):1065-7. doi: 10.1002/art.1780330802. No abstract available.
citation: Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Calabrese LH, Fauci AS, Leavitt RY, Lie JT, Lightfoot RW Jr, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum. 1990 Aug;33(8):1135-6. doi: 10.1002/art.1780330812. No abstract available.
citation: Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994 Feb;37(2):187-92. doi: 10.1002/art.1780370206.
citation: 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 Jun;59(6):478-82. doi: 10.1136/ard.59.6.478.
citation: Felson DT, Anderson JJ. Methodological and statistical approaches to criteria development in rheumatic diseases. Baillieres Clin Rheumatol. 1995 May;9(2):253-66. doi: 10.1016/s0950-3579(05)80189-x.
citation: Yates M, MacGregor AJ, Robson J, Craven A, Merkel PA, Luqmani RA, Watts RA. The association of vascular risk factors with visual loss in giant cell arteritis. Rheumatology (Oxford). 2017 Apr 1;56(4):524-528. doi: 10.1093/rheumatology/kew397.