The epidemiology and natural history of ANCA-associated vasculitis in the UK: a response to The UK Strategy for Rare Diseases

Introduction: Rare diseases have gained recognition over the past decade as an important area for health service improvement. They affect 1 in 17 people over a lifetime, consume 14% of the NHS budget, and are an important cause of illness and death[1]. In 2013, the Department of Health published for the first time a “UK Strategy for Rare Diseases” which identified 5 key recommendations for improving the lives of people with rare diseases, and included the need for epidemiological studies. 75% of rare diseases are genetic in origin, and have onset in childhood. However, rheumatologists provide care for people with a number of rare diseases, amounting to an important component of the 25% of rare diseases which are believed to be non-genetic and present in adulthood. One of the main challenges in studying rare disease, is the difficulty in finding enough people with the disease to study. Recent linkage of databases of primary and secondary care health records in the UK provide an opportunity to study representative samples, large numbers of people, and the breadth of healthcare provision. In this thesis, I report 4 epidemiological studies in routinely collected healthcare data, conducted in an exemplar rheumatic disease, ANCA-associated vasculitis. Methods: I used routinely collected healthcare data from local hospitals, a large database of UK general practice records, and linked hospital episode statistics to identify cases of ANCA-associated vasculitis. The specific questions addressed in the studies were: 1. What are the current incidence, prevalence and mortality of ANCA-associated vasculitis in the UK, stratified by age, sex and ethnic group? I addressed this question in a local hospital cohort, and then in linked primary and secondary care records in England. I used projections of the population structure in 20 years’ time to predict the expected number of incident and prevalent cases. 2. What is the natural history of the most common type of ANCA-associated vasculitis (granulomatosis with polyangiitis) prior to diagnosis, and are there opportunities to diagnose it sooner in primary or secondary care? I conducted a case-control study in a large database of primary care records, and attempted to develop a model for GPs that predicted the risk of a person having granulomatosis with polyangiitis, such as is advocated by the UK Strategy for Rare Diseases. 3. What are the strongest aetiological factors in granulomatosis with polyangiitis in the UK? I compared the frequency of possible aetiological exposures between cases and population-based controls in a large database of prospectively collected primary care data. Results: 1. There were about 1300 new cases of ANCA-associated vasculitis in the UK in 2015, more than previously thought. The incidence has been stable since 2000, however the disease is more common in older people, therefore due to predicted aging of the UK population there will be 34% more cases in 2035. We are not able to detect any differences in incidence rates between people from different ethnic groups, but our studies lacked power for this question. 2. People with granulomatosis with polyangiitis consulted their GP more than healthy people prior to their diagnosis. However, they consulted with a wide variety of symptoms, and none were highly predictive of the diagnosis. In addition, the lower the prevalence of the disease, the lower the positive predictive value of a diagnostic model. Granulomatosis with polyangiitis is rare, so even with an exceptionally well-performing model (with a sensitivity of 100% and a specificity of 90%) only 2 of every 10,000 people flagged as ‘at risk’ would have granulomatosis with polyangiitis, and the rest would have false positive results. 3. People with granulomatosis with polyangiitis were 5 times more likely than population-based controls to have a previous diagnosis of bronchiectasis, and 2-3 times more likely to have a previous diagnosis of an autoimmune disease or chronic renal impairment. Conclusions: 1. Although incidence appears stable, commissioners need to expand services to diagnose and treat people with GPA, and other adult-onset rare diseases, over the next 20 years due to the predicted increase in the proportion of the population in the age-groups at highest risk. 2. In particular, over the next 20 years, the age structure of the Black and Minority ethnic population in the UK is predicted to change to have many more people in older age-groups, and the UK medical community need to be alert to an expected emergence of significant numbers of Black and Minority ethnic people with ANCA-associated vasculitis. 3. Computerised prompts to alert GPs to consider a diagnosis of rare disease are unlikely to work. Resources to improve early diagnosis and treatment of ANCA-associated vasculitis would be better targeted at secondary care where the majority of cases have contact in the year before diagnosis. 4. The novel association of bronchiectasis with developing granulomatosis with polyangiitis raises a new hypothesis for bronchiectasis as a possible aetiological factor in granulomatosis with polyangiitis

Successfully dating rock art in Southern Africa using improved sampling methods and new characterization and pretreatment protocols

©2016 University of Arizona. This is the Author Accepted Manuscript. Please refer to any applicable publisher terms of use.Worldwide, dating rock art is difficult to achieve because of the frequent lack of datable material and the difficulty of removing contamination from samples. Our research aimed to select the paints that would be the most likely to be successfully radiocarbon dated and to estimate the quantity of paint needed depending on the nature of the paint and the weathering and alteration products associated with it. To achieve this aim, a two-step sampling strategy, coupled with a multi-instrument characterization (including SEM-EDS, Raman spectroscopy, and FTIR spectroscopy analysis) and a modified acid-base-acid (ABA) pretreatment, was created. In total, 41 samples were dated from 14 sites in three separate regions of southern Africa. These novel protocols ensure that the 14C chronology produced was robust and could also be subsequently applied to different regions with possible variations in paint preparation, geology, weathering conditions, and contaminants

Intra-dance variation among waggle runs and the design of efficient protocols for honey bee dance decoding

Noise is universal in information transfer. In animal communication, this presents a challenge not only for intended signal receivers, but also to biologists studying the system. In honey bees, a forager communicates to nestmates the location of an important resource via the waggle dance. This vibrational signal is composed of repeating units (waggle runs) that are then averaged by nestmates to derive a single vector. Manual dance decoding is a powerful tool for studying bee foraging ecology, although the process is time-consuming: a forager may repeat the waggle run 1- >100 times within a dance. It is impractical to decode all of these to obtain the vector; however, intra-dance waggle runs vary, so it is important to decode enough to obtain a good average. Here we examine the variation among waggle runs made by foraging bees to devise a method of dance decoding. The first and last waggle runs within a dance are significantly more variable than the middle run. There was no trend in variation for the middle waggle runs. We recommend that any four consecutive waggle runs, not including the first and last runs, may be decoded, and we show that this methodology is suitable by demonstrating the goodness-of-fit between the decoded vectors from our subsamples with the vectors from the entire dances

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

Objectives: To estimate the incidence, prevalence and mortality of Granulomatosis with polyangiitis (GPA) in the United Kingdom. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (CPRD-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. Incidence in children (aged <16 years) was 0.88 (95% CI 0.40-1.96), and adults 14.0 (95% CI 12.8-15.4). The incidence was lower in females (adjusted IRR 0.68; 95% CI 0.56-0.81) and highest in the 55-69 year age-group (adjusted IRR 9.5, 95% CI 6.9-13.0; reference group 0-39 years). Incidence was not significantly different in the Black / Minority Ethnic population compared to the white population (adjusted odds ratio 0.78, 95% CI 0.53-1.13, p=0.13). The prevalence in 2013 was 134.9 (121.3-149.6) /million. Mortality was 13.6% at 1-year, and higher in HES than CPRD-identified cases (Hazard ratio 3.16, 95% CI 2.19-4.56, p<0.001). Conclusions: 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 approximately 700 new cases of whom 95 will die within 12 months

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&lt;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&lt;0.001] and Chinese had a nearly 7-times increased chance [OR 6.8 (95% CI 2.6, 17.8), P&lt;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.</p

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

The incidence, prevalence and survival of systemic sclerosis in the UK Clinical Practice Research Datalink

Objective: To estimate the incidence, prevalence and survival of systemic sclerosis in the United Kingdom. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink (CPRD). We calculated the incidence and survival of systemic sclerosis between 1994 and 2013 and examined its association with age, sex, and socio-economic status. We calculated point prevalence on 1 July 2013, and examined its association with the same exposures. Results: We identified 1,327 cases with incident systemic sclerosis. Annual incidence was 19.4 per million person-years between 1994 and 2013. The incidence was 4.7 times higher in women than in men, was not influenced by socioeconomic status, and has remained stable over the 20 year study period. The peak age of onset was 55-69 years. Survival at 1, 5 and 10 years was 94.2%, 80.0% and 65.7% respectively. The prevalence was 307 (290-323) per million with the highest prevalence in the 70-84 years age group. We estimate there are currently 1180 new cases of systemic sclerosis each year in the UK, and 19,390 people living with systemic sclerosis. Due to the predicted growth and aging of the population, we predict a 24% increase in incident cases and 26% increase in prevalent cases in 20 years’ time. Conclusion: Our estimates of incidence and prevalence are higher than previously reported in the UK, but similar to recent USA and Swedish studies, and do not support a north-south gradient of the occurrence of systemic sclerosis in Europe

Can granulomatosis with polyangiitis be diagnosed earlier in primary care? A case-control study

Background: People with granulomatosis with polyangiitis (GPA) commonly describe long delays before diagnosis. Aim: To study the natural history of GPA prior to diagnosis using primary care data, and determine whether clinical features could be identified to help earlier diagnosis.DesignCase-control study using the Clinical Practice Research Datalink. Methods: We compared primary care activity and clinical features between cases and 10 matched controls. Results: We identified 757 cases and matched 7,546 controls. Compared to controls, cases had more GP consultations and overall healthcare activity in the five years prior to their diagnosis, with a marked increase in the year before diagnosis, and particularly in the last 3 months. However, consultations were mostly for symptoms that were not specifically related to GPA. In the year prior to diagnosis, the most frequent and strongly predictive clinical features of GPA were Ear Nose and Throat (ENT) symptoms (34.5% of cases, odds ratio (OR) 10.5, 95% confidence intervals (CI) 8.6-12.7), and general (constitutional) symptoms (21.5% of cases, OR 9.0, 95% CI 7.1-11.3). In the year before diagnosis a larger number of cases attended secondary care (382, 50.5%) than had records of clinical features of GPA. Conclusions: After discussing our findings, we conclude it would be difficult to identify cases of GPA earlier in primary care. Our results support a need for heightened awareness of this condition among secondary care clinicians, especially those assessing emergency admissions, and in the clinics which were most frequently attended by cases 3-12 months prior to diagnosis

A Systematic Review and Meta-Analysis of the Incidence Rate of Takayasu Arteritis

Objectives: Takayasu arteritis (TAK), is a rare autoimmune rheumatic disease causing large vessel vasculitis. Onset is typically between the ages of 20-30. It is associated with substantial morbidity and mortality, notably due to its effects on the cardiovascular system. It has a poorly understood global epidemiology. Our objective was to systematically review the available evidence in order to calculate the incidence rate of TAK. Methods: Three databases (Medline, PubMed and Embase) were searched in November 2019 and the results were screened by two reviewers. A random effects meta-analysis was then conducted in R to calculate the overall incidence rate. Heterogeneity was assessed using I2. The quality of the studies was assessed using an adapted Newcastle-Ottawa scale. Further sub-group analyses were performed by quality, sex, research setting and geographical location. Publication bias was assessed using a Begg’s funnel plot. Results: The incidence rate for TAK per million person-years with 95% confidence intervals was 1.11 per million person years (95% CI 0.70 – 1.76). The heterogeneity in the data was extremely high in all analyses, which suggests that there was considerable variation in incidence rates across the different populations studied. TAK was found to be more common in women (incidence rate 2.01 per million person-years, 95% CI 1.39-2.90). Conclusions: TAK is an extremely rare disease. It affects women more commonly than men. There is considerable variation in the incidence rate between populations. We suggest that future research should focus on discrete populations in order to better identify genetic and environmental risk factors

Long term outcomes of daily oral vs. pulsed intravenous cyclophosphamide in a non-trial setting in ANCA associated vasculitis

Objectives We aimed to compare risk of death, relapse, neutropenia and infection requiring hospital admission between unselected ANCA-associated vasculitis (AAV) patients according to whether cyclophosphamide induction was by daily oral (PO) or pulse intravenous (IV) route.Method We identified all newly-diagnosed AAV patients treated with PO or IV cyclophosphamide between March 2007 and June 2013. We used Cox and logistic regression models to compare mortality, relapse and adverse events, and adjusted these for age, renal function and other significant confounders.Results 57 patients received PO and 57 received IV cyclophosphamide. One year survival was 86.0% in PO and 98.2% in IV patients; all-time adjusted hazard ratio (HR) for PO compared to IV cyclophosphamide was 1.8 (95% CI 0.3-10.6, P=0.54). One-year relapse-free survival was 80.7% in PO compared to 87.3% in IV patients, all-time adjusted HR 3.8 (0.2-846, P=0.37). During the first 12 months neutropenia of ≤0.5x10⁹/L occurred in 9 (16%) PO and 0 (0%) IV cyclophosphamide patients (p=0.003). The number of patients admitted with one or more infections was 16 (28%) in the PO group and 9 (16%) in the IV group, adjusted OR 2.2 (0.6-8.6, p=0.23).Conclusions. We observed an increased risk of neutropenia, and a trend towards increased risk of death, and admission with infection with PO cyclophosphamide. This adds certainty to previous studies, indicating that PO administration induces greater marrow toxicity. Infection-related admissions within 12 months of starting cyclophosphamide were higher than in clinical trials, possibly reflecting the unselected nature of this cohort