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

Giant Cell Arteritis Clinical Trial

— DCVAS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01066208
• Other study ID #: ACREULAR001
• Status: Recruiting
• Phase: N/A
• First received: February 9, 2010
• Last updated: August 18, 2016
• Start date: January 2011
• Est. completion date: December 2018

Study information

• Verified date: August 2016
• Source: University of Oxford
• Contact: Raashid A Luqmani
• Phone: +44 1865 738106
• Email: raashid.luqmani[@]ndorms.ox.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Observational

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3588
• Est. completion date: December 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Arteritis
• Churg Strauss Syndrome
• Churg-Strauss Syndrome
• Giant Cell Arteritis
• Granulomatosis with Polyangiitis
• Microscopic Polyangiitis
• Polyarteritis Nodosa
• Polymyalgia Rheumatica
• Systemic Vasculitis
• Takayasu Arteritis
• Vasculitis
• Wegener's Granulomatosis

Locations

Country	Name	City	State
Argentina	Ramos Mejia Hospital, University of Buenos Aires	Buenos Aires
Argentina	Hospital Interzonal San Juan Bautista	San Fernando del Valle de Catamarca	Catamarca
Australia	ANU Medical Centre	Canberra	Australian Capital Territory
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Austria	Medical University Innsbruck	Innsbruck
Belgium	University Hospitals Leuven	Leuven
Canada	University of Calgary	Calgary
Canada	St Joseph's Healthcare	Hamilton	Ontario
Canada	McGill University	Montreal	Quebec
Canada	St Joseph's Healthcare London, Ontario	Ontario
Canada	University of Ottawa	Ottawa	Ontario
Canada	Sherbrooke University Hospital Centre	Sherbrooke	Quebec
Canada	Mount Sinai Hospital, Toronto	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
China	Peking Union Medical College Hospital, Beijing	Beijing
Czech Republic	General University Hospital	Prague
Czech Republic	General University Hospital, Prague	Prague
Denmark	Rigshospitalet	Copenhagen
Egypt	Assiut University, Assiut University Hospitals	Assiut
Egypt	Cairo University, Kasr El Ainy Hospital	Cairo
Finland	Helsinki University Central Hospital	Helsinki
France	Cochin Hospital, Université Paris-descartes	Paris
Germany	Universitätsklinikum Jena	Jena
Germany	University of Schleswig-Holstein	Luebeck
Germany	Universitätsklinikum Münster	Münster
Germany	Kreiskliniken Esslingen	Plochingen
Germany	University Hospital Tübingen	Tübingen
Hungary	University of Debrecen Medical and Health Science Center	Debrecen
India	Postgraduate Institute of Medical Education and Research, Chandigarh	Chandigarh
India	Nizam's Institute of Medical Sciences, Hyderabad	Hyderabad
India	Chatrapathi Shahuji Maharaj Medical Center, Lucknow (IProcess)	Lucknow	Uttar Pradesh
India	Medanta, Delhi	New Delhi
India	Christian Medical College & Hospital, Vellore	Vellore
Ireland	Cork University Hospital	Cork
Ireland	St. Vincent's University Hospital, Dublin	Dublin 4
Italy	University of Parma	Parma
Italy	Arcispedale Santa Maria Nuova	Reggio Emilia
Italy	Santa Maria Nuova Hospital, Reggio Emilia	Reggio Emilia
Japan	Chiba University	Chiba
Japan	Kagawa University Hospital	Kagawa
Japan	Kameda Medical Centre, Kamogawa	Kamogawa City	Chiba prefecture
Japan	St. Marianna University Hospital	Kanagawa
Japan	Kanazawa University Hospital	Kanazawa
Japan	Saitama Medical University	Kawagoe	Saitama Prefecture
Japan	Kyorin University Hospital	Mitaka	Tokyo Prefecture
Japan	Miyazaki University Hospital	Miyazaki City	Miyazaki Prefecture
Japan	Okayama University Hospital	Okayama
Japan	Kitano Hospital	Osaka
Japan	Juntendo University Koshigaya Hospital	Saitama
Japan	Jichi Medical University Hospital	Tochigi-ken
Japan	University Tokyo Hospital	Tokyo
Japan	Tsukuba University Hospital	Tsukuba	Ibaraki Prefecture
Korea, Republic of	Seoul National University Hospital	Seoul
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City
Mexico	Instituto Nacional de Enfermedades Respiratorias	Mexico City
Netherlands	VU University Medical Center	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
New Zealand	Auckland District Health Board	Auckland
New Zealand	Waitemata District Health Board, North Shore Hospital	Auckland
New Zealand	University of Otago, Christchurch	Christchurch	Canterbury
New Zealand	Waikato District Health Board	Hamilton
Norway	Hospital of Southern Norway	Kristiansand
Norway	The University Hospital of Northern Norway, Tromsø	Tromsø
Poland	University of Jagiellonian	Kraków
Portugal	Hospital Garcia de Orta, Almada	Almada
Portugal	Santa Maria Hospital, Lisbon	Lisbon
Portugal	Hospital Santo Antonio, Porto	Porto
Russian Federation	First Moscow State Medical University	Moscow
Slovenia	University Medical Centre Ljubljana	Ljubljana
Spain	Clinic Barcelona Hospital Universitari	Barcelona	Catalonia
Sri Lanka	University of Colombo	Columbo 8
Sweden	Lund University	Lund
Sweden	Karolinska Institute, Stockholm	Stockholm
Sweden	Linköping University	Stockholm
Sweden	Umeå University	Umeå
Sweden	Uppsala University Hospital	Uppsala
Switzerland	University Hospital Basel	Basel
Switzerland	Immunologie-Zentrum Zurich	Zurich
Turkey	Hacettepe University	Ankara
Turkey	Fatih University Medical Faculty	Istanbul
Turkey	Haydarpasa Education and Research Hospital	Istanbul
Turkey	Istanbul University, Cerrahpasa Medical School	Istanbul
Turkey	Istanbul University, Istanbul Medical School	Istanbul
Turkey	Marmara University Medical School	Istanbul
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Basildon and Thurrock University Hospitals NHS Foundation Trust	Basildon	Essex
United Kingdom	University of Birmingham	Birmingham
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	North Cumbria University Hospitals, The Cumberland Infirmary	Carlisle	Cumbria
United Kingdom	Epsom and St Helier University Hospitals NHS Trust	Carshalton	Surrey
United Kingdom	Dudley Group of Hospitals, NHS FT	Dudley
United Kingdom	NHS Greater Glasgow & Clyde, Gartnavel Hospital	Glasgow	Scotland
United Kingdom	Ipswich Hospital NHS Trust	Ipswich	Suffolk
United Kingdom	NHS Fife, Whyteman's Brae Hospital, Windygates	Kirkcaldy	Fife
United Kingdom	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London
United Kingdom	University of Manchester, Manchester Royal Infirmary	Manchester
United Kingdom	Norfolk and Norwich University Hospital	Norwich
United Kingdom	Nottingham University Hospitals NHS Trust (QMC)	Nottingham
United Kingdom	Nuffield Orthopaedic Centre	Oxford
United Kingdom	Oxford University Hospitals NHS Trust (The Churchill Hospital)	Oxford
United Kingdom	Royal Berkshire NHS Trust	Reading
United Kingdom	Queen's Hospital	Romford	Essex
United Kingdom	Heatherwood & Wexham Park Hospitals NHS Foundation Trust	Slough
United Kingdom	Southampton University Hospitals NHS Trust	Southampton
United Kingdom	Southend University Hospital NHS Trust	Westcliff-on-Sea	Essex
United Kingdom	York Hospital NHS Foundation Trust	York
United States	University of Michigan, Internal Medicine	Ann Arbor	Michigan
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Vasculitis Center, Boston University School of Medicine	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	Dartmouth-Hitchcock Medical Centre, Lebanon, NH	Lebanon	New Hampshire
United States	Cedars-Sinai Medical Center, LA	Los Angeles	California
United States	New York University Langone Medical Centre	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University Medical Center	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California

Sponsors (4)

Lead Sponsor	Collaborator
University of Oxford	American College of Rheumatology, The European League Against Rheumatism (EULAR), The Vasculitis foundation

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  China,  Czech Republic,  Denmark,  Egypt,  Finland,  France,  Germany,  Hungary,  India,  Ireland,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Norway,  Poland,  Portugal,  Russian Federation,  Slovenia,  Spain,  Sri Lanka,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

References & Publications (7)

Felson DT, Anderson JJ. Methodological and statistical approaches to criteria development in rheumatic diseases. Baillieres Clin Rheumatol. 1995 May;9(2):253-66. Review. — View 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. — View 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. — View 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. Review. — View 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. — View Citation

Singh JA, Solomon DH, Dougados M, Felson D, Hawker G, Katz P, Paulus H, Wallace C; Classification and Response Criteria Subcommittee of the Committee on Quality Measures, American College of Rheumatology. Development of classification and response criteria for rheumatic diseases. Arthritis Rheum. 2006 Jun 15;55(3):348-52. — View Citation

Sørensen 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Develop new diagnostic and classification criteria for ANCA associated vasculitis and polyarteritis nodosa		3 years	No

External Links

•   Website for European Vasculitis Study Group (EUVAS)