Incidence of primary large vessel vasculitis in Norfolk, UK from 2011 to 2020.

OBJECTIVES: To report the annual incidence of primary large vessel vasculitis (LVV) in the adult population of Norfolk County, UK, including giant cell arteritis (GCA) (in those ≥50 years) and Takayasu arteritis (TAK). METHODS: Individuals diagnosed by histology or imaging who lived in NR1-NR30 postcode districts were included. Validated criteria from 1990 and 2022 were applied for final classification. Population data were available from the Office of National Statistics, UK. RESULTS: 270 individuals were diagnosed with primary LVV over 4.7 million person-years. The annual incidence (95% CI) of primary LVV was 57.5 (50.8, 64.7)/million person-years in the adult population. 227 and 244 individuals were diagnosed with GCA over ~2.5 million person-years using 1990 and 2022 criteria, respectively. The annual incidence (95% CI) of GCA was 91.6 (80.0, 104.3)/million person-years aged ≥50 years using 1990 criteria and 98.4 (86.4, 111.6)/million person-years aged ≥50 years using 2022 criteria. 13 and 2 individuals were diagnosed with TAK over 4.7 million person-years. The annual incidence (95% CI) of TAK was 2.8 (1.5, 4.7)/million person-years using 1990 criteria and 0.4 (0.0, 1.4)/million person-years using 2022 criteria, in the adult population. The incidence of GCA rose sharply in 2017 coincident with the introduction of a fast-track pathway and fell during the pandemic when the pathway was disrupted. CONCLUSIONS: This is the first study that reports the incidence of objectively verified primary LVV in the adult population. The incidence of GCA may be affected by the availability of diagnostic pathways. The use of the 2022 classification criteria results in a rise in the classification of GCA and fall in that of TAK.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for microscopic polyangiitis.

OBJECTIVE: To develop and validate classification criteria for microscopic polyangiitis (MPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for MPA consisted of 149 cases of MPA and 408 comparators. The validation set consisted of an additional 142 cases of MPA and 414 comparators. From 91 candidate items, regression analysis identified 10 items for MPA, 6 of which were retained. The final criteria and their weights were as follows: perinuclear antineutrophil cytoplasmic antibody (ANCA) or anti-myeloperoxidase-ANCA positivity (+6), pauci-immune glomerulonephritis (+3), lung fibrosis or interstitial lung disease (+3), sino-nasal symptoms or signs (-3), cytoplasmic ANCA or anti-proteinase 3 ANCA positivity (-1) and eosinophil count ≥1×109/L (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having MPA with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 91% (95% CI 85% to 95%) and the specificity was 94% (95% CI 92% to 96%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for MPA are now validated for use in clinical research.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis.

OBJECTIVE: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1×109 /L (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% CI 87% to 96%) and the specificity was 94% (95% CI 89% to 97%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis.

OBJECTIVE: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. RESULTS: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1×109/L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3-ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and haematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% CI 77% to 91%) and the specificity was 99% (95% CI 98% to 100%). CONCLUSION: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis demonstrate strong performance characteristics and are validated for use in research.

2022 American College of Rheumatology/EULAR classification criteria for Takayasu arteritis.

OBJECTIVE: To develop and validate new classification criteria for Takayasu arteritis (TAK). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate criteria items, (2) collection of candidate items present at diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based classification score in a development data set and (6) validation in an independent data set. RESULTS: The development data set consisted of 316 cases of TAK and 323 comparators. The validation data set consisted of an additional 146 cases of TAK and 127 comparators. Age ≤60 years at diagnosis and imaging evidence of large-vessel vasculitis were absolute requirements to classify a patient as having TAK. The final criteria items and weights were as follows: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of ≥20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1) and abdominal aorta plus renal or mesenteric involvement (+3). A patient could be classified as having TAK with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the model area under the curve was 0.97 (95% CI 0.94 to 0.99) with a sensitivity of 93.8% (95% CI 88.6% to 97.1%) and specificity of 99.2% (95% CI 96.7% to 100.0%). CONCLUSION: The 2022 American College of Rheumatology/EULAR classification criteria for TAK are now validated for use in research.

2022 American College of Rheumatology/EULAR classification criteria for giant cell arteritis.

OBJECTIVE: To develop and validate updated classification criteria for giant cell arteritis (GCA). METHODS: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in six phases: (1) identification of candidate items, (2) prospective collection of candidate items present at the time of diagnosis, (3) expert panel review of cases, (4) data-driven reduction of candidate items, (5) derivation of a points-based risk classification score in a development data set and (6) validation in an independent data set. RESULTS: The development data set consisted of 518 cases of GCA and 536 comparators. The validation data set consisted of 238 cases of GCA and 213 comparators. Age ≥50 years at diagnosis was an absolute requirement for classification. The final criteria items and weights were as follows: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate ≥50 mm/hour or C reactive protein ≥10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders or neck, jaw or tongue claudication, new temporal headache, scalp tenderness, temporal artery abnormality on vascular examination, bilateral axillary involvement on imaging and fluorodeoxyglucose-positron emission tomography activity throughout the aorta (+2 each). A patient could be classified as having GCA with a cumulative score of ≥6 points. When these criteria were tested in the validation data set, the model area under the curve was 0.91 (95% CI 0.88 to 0.94) with a sensitivity of 87.0% (95% CI 82.0% to 91.0%) and specificity of 94.8% (95% CI 91.0% to 97.4%). CONCLUSION: The 2022 American College of Rheumatology/EULAR GCA classification criteria are now validated for use in clinical research.

Is There Still a Role of Plasma Exchange in the Current Management of ANCA-Associated Vasculitides?

PURPOSE OF REVIEW: Plasma exchange (PLEX) is often recommended as an adjunctive therapy for patients with ANCA-associated vasculitis (AAV) in the setting of rapidly progressive glomerulonephritis or diffuse alveolar haemorrhage. Since ANCAs are pathogenic, it seems a reasonable and justified approach to remove them through therapeutic PLEX, as despite advances in immunosuppressive therapy regimens, AAV is associated with significant morbidity and death. However, the association between ANCA levels and mortality or disease activity is uncertain. In addition, any treatment must be judged on the potential risks and benefits of its use. Here, we summarise the current data on PLEX usage in patients with AAV. RECENT FINDINGS: The largest randomised trial to date the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) study failed to show added benefit for PLEX on the prevention of death or end-stage renal failure (ESRF) for the management of patients with severe AAV. However, there is a possibility that PLEX delays dialysis dependence and ESRF in the early stages of the disease. Regardless of whether this is only for 3 to 12 months, this could be of clinical significance and a substantial improvement in patient's quality of life. Cost utility analysis and trials including patient-centred outcomes are required to evaluate the use of PLEX. Furthermore, ascertaining those at high risk of developing ESRF could help identify those who may benefit from PLEX the most, and further insights are required in setting of diffuse alveolar haemorrhage.

Pulmonary involvement in primary systemic vasculitides.

OBJECTIVES: This study describes the spectrum and initial impact of pulmonary manifestations in the primary systemic vasculitides. METHODS: Description and comparison of pulmonary manifestations in adults with Takayasu's arteritis (TAK), GCA, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA), polyarteritis nodosa (PAN) and IgA vasculitis (IgAV), using data collected within the Diagnostic and Classification Criteria in Vasculitis study. RESULTS: Data from 1952 patients with primary vasculitides were included: 170 TAK, 657 GCA, 555 GPA, 223 MPA, 146 EGPA, 153 IgAV and 48 PAN. Pulmonary manifestations were observed in patients with TAK (21.8%), GCA (15.8%), GPA (64.5%), MPA (65.9%), EGPA (89.0%), PAN (27.1%) and IgAV (5.9%). Dyspnoea occurred in patients with TAK (14.7%), GCA (7.8%), GPA (41.8%), MPA (43.5%), EGPA (65.8%), PAN (18.8%) and IgAV (2.6%). Cough was reported in TAK (7.6%), GCA (9.3%), GPA (34.8%), MPA (37.7%), EGPA (55.5%), PAN (16.7%) and IgAV (3.3%). Haemoptysis occurred mainly in patients with ANCA-associated vasculitis (AAV). Fibrosis on imaging at diagnosis was documented in GPA (1.9%), MPA (24.9%) and EGPA (6.3%). Only patients with AAV (GPA 2.7%, MPA 2.7% and EGPA 3.4%) required mechanical ventilation. At 6 months, the presence of at least one pulmonary item in the Vasculitis Damage Index was observed in TAK (4.1%), GCA (3.3%), GPA (15.4%), MPA (28.7%), EGPA (52.7%), PAN (6.2%) and IgAV (1.3%). CONCLUSION: Pulmonary manifestations can occur in all primary systemic vasculitides, but are more frequent and more often associated with permanent damage in AAV.

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.

The value of case reports in democratising evidence from resource-limited settings: results of an exploratory survey.

BACKGROUND: Following a knowledge management analysis, Médecins Sans Frontières (MSF) - a medical humanitarian non-governmental organisation (NGO) - identified significant loss of medical knowledge from the field, owing primarily to the absence of a platform on which to share clinical lessons learned in humanitarian and resource-limited settings (HRLS). Wishing to address these missed opportunities to retain important scientific and pragmatic knowledge, the NGO has begun to actively encourage its clinicians to publish case reports/series that bring new and/or practical insights of benefit to patients and population groups. In parallel, we wished to obtain a clearer understanding of how case reports (CRs)/series can best play their role as 'first-line evidence' from HRLS, especially in areas suffering from a significant lack of data. METHODS: We developed a survey with closed and open questions on 'The value of CRs from HRLS' to explore primarily (1) the reasons why this form of evidence from HRLS is often lacking, (2) what makes a case report/series worth sharing with the wider global health community, and (3) how we can ensure that published case reports/series reach their target audience. RESULTS: Over a 6-month period, 1115 health professionals responded to the survey. Participants included clinicians and public health specialists from all over the world, with a majority based in Africa. The main reason cited for the dearth of CRs from HRLS was that practitioners are simply not writing and/or submitting reports (as versus having their papers rejected) due mainly to (1) a lack of skills and (2) time constraints. A large majority of respondents felt the CRs are a valuable tool for HRLS given their ability to discuss how cases are managed with rudimentary means as well as to draw attention to emerging or underestimated public health problems and neglected populations. CONCLUSION: We conclude that the clinical knowledge gained in resource-challenged settings is being underutilised in the interest of patients and global health. Consequently, clinicians in HRLS need greater access to basic training in scientific investigation and writing in addition to awareness as to the potential value of sharing their clinical experience with a view to broadening evidence production from high-income to low-income settings.

Novel insights into the aetiology of granulomatosis with polyangiitis-a case-control study using the Clinical Practice Research Datalink.

Objectives: We aimed to provide insights into the aetiology of granulomatosis with polyangiitis (GPA), by conducting a large case-control study using a general population-based, prospectively collected database of healthcare records. Methods: We compared all incident cases of GPA in the Clinical Practice Research Datalink 1990-2014, with up to 10 age-, sex- and general practice-matched controls. We identified potential risk factors, recorded numbers of cases and controls exposed to each, and calculated odds ratios (ORs) using conditional logistic regression. Our main analysis excluded data recorded during 1 year before diagnosis, to prevent early symptoms being mistaken for risk factors. Results: We identified 757 people with GPA and matched 7546 controls. People with GPA were five times more likely to have a previous diagnosis of bronchiectasis (OR = 5.1, 95% CI: 2.7, 9.4; P < 0.0001), and these effects remained stable in diagnoses recorded >5 years prior to diagnosis. People with GPA were two to three times more likely than controls to have previous diagnoses of autoimmune diseases or chronic renal impairment, and these effects also remained stable >5 years prior to diagnosis. People with GPA were more likely to have a diagnosis of pulmonary fibrosis (OR = 5.7, 95% CI: 1.7, 19.5; P = 0.01) and sinus infections (OR = 2.7, 95% CI: 1.8, 4.2; P < 0.0001) recorded in the 3 years before diagnosis, but not before this. We also found former smoking, some medications and higher socio-economic status significantly, but less strongly, associated. Conclusion: We found novel long-term associations between GPA and pre-existing bronchiectasis and autoimmune diseases.

Global ethnic and geographic differences in the clinical presentations of anti-neutrophil cytoplasm antibody-associated vasculitis.

Objectives: There are few data on clinical profiles of ANCA-associated vasculitis (AAV) in different ethnic populations. The aim of this study was to examine the differences in the ANCA type and clinical features of AAV between populations using the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) dataset. Methods: The DCVAS is an international, multicentre, observational study recruiting in 133 sites. Eight ethnic categories were analysed: Northern European, Caucasian American, Southern European, Middle Eastern/Turkish, Chinese, Japanese, Indian subcontinent and other. ANCA type was categorized as myeloperoxidase (MPO), PR3 and ANCA negative. Organ system involvement was recorded using a standard dataset. Differences were analysed by chi-squared tests using a Bonferroni correction and logistic regression (adjusting for age and sex). Northern European was the reference population. Results: Data from 1217 patients with AAV were available and the 967 (79.5%) patients recruited by rheumatology departments were analysed to reduce confounding by recruitment specialty. There were differences in ANCA type between ethnic categories (P < 0.001): MPO-ANCA was more common than PR3-ANCA in Japanese, Chinese and Southern Europeans; PR3-ANCA was more common in the other groups. Compared with Northern Europeans, Japanese had a nearly 60-fold increased chance of having MPO-ANCA (vs PR3-ANCA) [odds ratio (OR) 59.2 (95% CI 8.0, 440.7), P < 0.001] and Chinese had a nearly 7-times increased chance [OR 6.8 (95% CI 2.6, 17.8), P < 0.001]. Ophthalmologic and otorhinolaryngologic involvement were less common in Japanese and Chinese populations than Northern Europeans; otherwise, there were few differences in organ involvement between ethnic groups. Conclusion: This study confirms the previously observed differential occurrence of MPO-AAV and PR3-AAV between different ethnic groups.

The association of vascular risk factors with visual loss in giant cell arteritis.

Objective: Blindness is a recognized complication of GCA; however, the frequency of and risk factors for this complication have not been firmly established. The aim of this study was to examine the incidence and determinants of blindness in patients with GCA, using a large international cohort. Methods: The analysis was conducted among subjects recruited into the Diagnosis and Classification Criteria in Vasculitis Study. The study captures consecutive patients presenting to clinic-based physicians. New-onset blindness was assessed 6 months after diagnosis by completion of the Vasculitis Damage Index. Logistic regression analysis was used to assess the association between blindness and clinical variables. Results: Of 433 patients with GCA from 26 countries, 7.9% presented with blindness in at least one eye at 6 months. Risk factors identified at baseline for blindness at 6 months were identified and included prevalent stroke [odds ratio (OR) = 4.47, 95% CI: 1.30, 15.41] and peripheral vascular disease (OR = 10.44, 95% CI: 2.94, 37.03). Conclusion: This is the largest study to date of subjects with incident GCA and confirms that blindness remains a common complication of disease and is associated with established vascular disease.Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT01066208.

The incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK Clinical Practice Research Datalink.

Objective: To estimate the incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (HES). We calculated incidence rate ratios, adjusted for age, gender and ethnicity, using Poisson regression. Results: We identified 462 cases diagnosed between 1997 and 2013. Our overall estimate of incidence was 11.8 (95% CI: 10.7, 12.9)/million person-years. The incidence was 0.88 (95% CI: 0.40, 1.96) in children (aged <16 years) and 14.0 (95% CI: 12.8, 15.4) in adults. The incidence was lower in females (adjusted incidence rate ratio = 0.68; 95% CI: 0.56, 0.81) and highest in the 55-69 year age group (adjusted incidence rate ratio = 6.8, 95% CI: 4.9, 9.6; reference group 16-39 years). The incidence was not significantly different in the Black/Minority Ethnic population from that in the White population (adjusted odds ratio = 0.78, 95% CI: 0.53, 1.13, P = 0.13). The prevalence in 2013 was 134.9 (95% CI: 121.3, 149.6)/million. Mortality was 13.6% at 1-year, and higher in the HES- than in the Clinical Practice Research Datalink-identified cases (hazard ratio = 3.16, 95% CI: 2.19, 4.56, P < 0.001). Conclusion: By combining primary and secondary care datasets, we have found the incidence and mortality of granulomatosis with polyangiitis to be higher than previously reported. We predict that at present each year in the UK there will be ∼700 new cases, of whom 95 will die within 12 months.

Are the 1990 American College of Rheumatology vasculitis classification criteria still valid?

Objectives: Advances in diagnostic techniques have led to better distinction between types of vasculitis, potentially affecting the utility of the 1990 ACR classification criteria for vasculitis. This study tested the performance of these criteria in a contemporary vasculitis cohort. Methods: The Diagnosis and Classification in Vasculitis Study provided detailed clinical, serological, pathological and radiological data from patients with primary systemic vasculitis and clinical context-specific comparator conditions. Fulfilment of six ACR criteria sets and their diagnostic performance was evaluated in patients with a given type of vasculitis and its comparator conditions. Results: Data from 1095 patients with primary systemic vasculitis and 415 with comparator conditions were available. For classification, sensitivities and specificities for ACR classification criteria were, respectively, 81.1% and 94.9% for GCA; 73.6% and 98.3% for Takayasu's arteritis; 65.6% and 88.7% for granulomatosis with polyangiitis; 57.0% and 99.8% for eosinophilic granulomatosis with polyangiitis; 40.6% and 87.8% for polyarteritis nodosa; 28.9% and 88.5% for microscopic polyangiitis; and 72.7% and 96.3% for IgA-vasculitis. Overall sensitivity was 67.1%. Of cases identified by their respective criteria, 16.9% also met criteria for other vasculitides. Diagnostic specificity ranged from 64.2 to 98.9%; overall, 113/415 comparators (27.2%) fulfilled at least one of the ACR classification criteria sets. Conclusion: Since publication of the ACR criteria for vasculitis, the sensitivity for each type of vasculitis, except GCA, has diminished, although the specificities have remained high, highlighting the need for updated classification criteria.

Incidence of ANCA-associated vasculitis in a UK mixed ethnicity population.

OBJECTIVES: We aimed to estimate the incidence of ANCA-associated vasculitis in the UK and how this varied by ethnic group. METHODS: We identified incident cases of ANCA-associated vasculitis between March 2007 and June 2013 in the Nottingham-Derby urban area from medical records using multiple sources. We derived the denominator population from the 2011 census, and we calculated incidence rate ratios using Poisson regression. RESULTS: Overall, we identified 107 cases of ANCA-associated vasculitis, giving an incidence of 23.1 per million person-years (95% CI: 18.9, 27.9). The incidence among the white population was 25.8 per million person-years (95% CI: 21.0, 31.3) and among the black and minority ethnic (BME) population 8.4 per million person-years (95% CI: 3.1, 18.3). After adjustment for age and sex, the difference between ethnic groups was not statistically significant (incidence rate ratio 0.7, 95% CI: 0.3, 1.5, P = 0.3). CONCLUSION: Overall, the incidence of ANCA-associated vasculitis was similar to other epidemiological studies. Crude incidence rates were lower in the BME than in the white population, but this was partly explained by the older age profile among the white compared with BME population.

Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

HLA allele variation as a potential explanation for the geographical distribution of granulomatosis with polyangiitis.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is a rare autoimmune systemic vasculitis considered to result from the interaction of environmental factors with a genetically predisposed host. The HLA-DPB1*0401 allele, the PI*Z allele of the gene encoding α1-antitrypsin (SERPINA1) and the proteinase 3 (PRTN3) gene have been associated with GPA. The incidence of GPA is lower in non-Caucasian populations and has been associated with higher latitude. Our aim was to determine whether variation in population carrier frequency of the HLA-DPB1*0401 and PI*Z alleles could explain in part the variation in GPA incidence between countries. METHODS: We systematically identified published reports on the incidence of GPA and used previously published data on the frequency of HLA-DBP1*0401 and PI*Z alleles. The relationship between GPA incidence, latitude and population HLA-DPB1*0401 and PI*Z allele frequencies was assessed by linear regression. RESULTS: On multivariate analysis GPA incidence was associated with HLA-DPB1*0401 allele frequency (P = 0.001) but not with PI*Z allele frequency or latitude. CONCLUSION: HLA-DPB1*0401 is a GPA susceptibility allele and HLA-DPB1*0401 population allele frequencies may help explain variations in GPA incidence described in the literature.