Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids

Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans

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

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

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

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

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

Outcomes and compliance with standards of care in ANCA-associated vasculitis: insights from a large multi-region audit

Objectives: We aimed to conduct a large audit of routine care for patients with ANCA-associated vasculitis (AAV). Methods: We invited all 34 hospitals within one health region in England to undertake a retrospective case note audit of all patients newly-diagnosed or treated with Cyclophosphamide or Rituximab for AAV April 2013-December 2014. We compared clinical practice to the BSR guideline for the management of adults with AAV, and use of Rituximab to the NHS England commissioning policy and NICE Technology Appraisal. Results: We received data from 213 patients. Among 130 newly diagnosed patients, delay from admission to diagnosis ranged from 0-53 days (median 6, IQR 3-10.5) for those diagnosed as in-patients. BVAS score was recorded in 8% at diagnosis. Remission at 6 months was achieved in 83% of patients. 1-year survival was 91.5%. 130 patients received Cyclophosphamide for new-diagnosis or relapse. The correct dose of i.v. cyclophosphamide (within 100mg of the target dose calculated for age, weight and creatinine) was administered in 58%. 25% of patients had an infection requiring hospital admission during or within 6 months of completing their cyclophosphamide therapy. 76 patients received Rituximab for new-diagnosis or relapse. 97% patients met NHS England or NICE eligibility criteria. PJP prophylaxis (recommended in the summary of product characteristics) was given in only 65% of patients. Conclusion: We identified opportunities to improve care, including compliance with safety standards for delivery of cyclophosphamide. Development of a national treatment protocol / checklist to reduce this heterogeneity in care should be considered as a priority

Validation of methods to identify people with idiopathic inflammatory myopathies using hospital episode statistics

ObjectiveHospital episode statistics (HES) are routinely recorded at every hospital admission within the National Health Service (NHS) in England. This study validates diagnostic ICD-10 codes within HES as a method of identifying cases of idiopathic inflammatory myopathies (IIMs).MethodsAll inpatient admissions at one NHS Trust between 2010 and 2020 with relevant diagnostic ICD-10 codes were extracted from HES. Hospital databases were used to identify all outpatients with IIM, and electronic care records were reviewed to confirm coding accuracy. Total hospital admissions were calculated from NHS Digital reports. The sensitivity and specificity of each code and code combinations were calculated to develop an optimal algorithm. The optimal algorithm was tested in a sample of admissions at another NHS Trust.ResultsOf the 672 individuals identified by HES, 510 were confirmed to have IIM. Overall, the positive predictive value (PPV) was 76% and sensitivity 89%. Combination algorithms achieved PPVs between 89 and 94%. HES can also predict the presence of IIM-associated interstitial lung disease (ILD) with a PPV of 79% and sensitivity of 71%. The optimal algorithm excluded children (except JDM code M33.0), combined M33.0, M33.1, M33.9, M36.0, G72.4, M60.8 and M33.2, and included M60.9 only if it occurred alongside an ILD code (J84.1, J84.9 or J99.1). This produced a PPV of 88.9% and sensitivity of 84.2%. Retesting this algorithm at another NHS Trust confirmed a high PPV (94.4%).ConclusionIIM ICD-10 code combinations in HES have high PPVs and sensitivities. Algorithms tested in this study could be applied across all NHS Trusts to enable robust and cost-effective whole-population research into the epidemiology of IIM