Burden of comorbidity in systemic lupus erythematosus in the UK, 1999–2012

Objective: To estimate the comorbidity associated with systemic lupus erythematosus (SLE) in the UK during 1999–2012. Methods: A retrospective cohort study using the UK Clinical Practice Research Datalink was conducted. Prevalent cases of SLE were matched by age, sex, and practice to 4 controls. The incidence of cardiovascular disease (CVD), stroke, end-stage renal failure (ESRF), cancer, osteoporosis, and infection were calculated per 1,000 person-years during the study period and compared to controls using Poisson regression to obtain incidence rate ratios (IRRs). IRRs were adjusted for baseline age, sex, body mass index, smoking status, alcohol intake, hypertension, hyperlipidemia, Charlson Index scores, and prednisolone use. Age- and sex-specific incidence rates were calculated. Results: When comparing the 7,732 prevalent cases of SLE with 28,079 matched controls, the unadjusted IRR was 1.98 (95% confidence interval [95% CI] 1.69–2.31) for CVD, 1.81 (95% CI 1.49–2.19) for stroke, 7.81 (95% CI 4.68–13.05) for ESRF, 1.28 (95% CI 1.17–1.40) for cancer, 2.53 (95% CI 2.27–2.82) for osteoporosis, and 1.49 (95% CI 1.40–1.58) for infection. After adjustment, the rates remained significantly higher in cases. Men with SLE had higher rates of CVD, stroke, and cancer, whereas women had higher rates of infection and osteoporosis. Those at younger ages were at the greatest relative risk compared with controls. Cases had significantly higher Charlson Index scores at baseline. Conclusion: People with SLE in the UK have a greater burden of comorbidity and are more likely to develop CVD, stroke, ESRF, cancer, osteoporosis, and infection than people of the same age and sex

The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012

Objectives: To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in the UK over the period 1999–2012. Methods: A retrospective cohort study using the Clinical Practice Research Datalink (CPRD). The incidence was calculated per 100 000 person-years and the prevalence was calculated per 100 000 people for the period 1999–2012 and stratified by year, age group, gender, region and ethnicity. Three definitions of SLE were explored: (1) systemic lupus, (2) a fully comprehensive definition of lupus including cutaneous only lupus and (3) requiring supporting evidence of SLE in the medical record. Results: Using our primary definition of SLE, the incidence during the study period was 4.91/100 000 person-years (95% CI 4.73 to 5.09), with an annual 1.8% decline (p<0.001). In contrast, the prevalence increased from 64.99/100 000 in 1999 (95% CI 62.04 to 67.93) (0.065%) to 97.04/100 000 in 2012 (95% CI 94.18 to 99.90) (0.097%). SLE was six times more common in women. The peak age of incidence was 50–59 years. There was regional variation in both incidence and prevalence. People of Black Caribbean ethnicity had the highest incidence and prevalence. Alternative definitions of SLE increased (definition 2) or decreased (definition 3) estimates of incidence and prevalence, but similar trends were found. Conclusions: The incidence of SLE has been declining but the prevalence has been increasing in the UK in recent years. Age, gender, region and ethnicity are risk factors for SLE. This is the first study to report ethnic differences on the incidence and prevalence of SLE using the CPRD

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Background Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. Methods We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. Results 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. Conclusions We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults

Paramedics’ perceptions of the care they provide to people who self-harm: A qualitative study using evolved grounded theory methodology

BACKGROUND:Self-harm (SH) accounts for over 5% of the workload of emergency ambulance services, and therefore Paramedics are often the first health professional in contact with people who SH. The authors of this paper have reported elsewhere the significant gaps in our understandings which exist surrounding this early care interaction, and some of the challenges paramedics and opportunities in paramedic care for people who SH. This study aimed to explore paramedics' perceptions of caring for those who SH using Evolved Grounded Theory Methodology. METHODS:This study took place between 2014-2016 in one UK ambulance service covering a population of three million people. Semi structured interviews were conducted, purposively sampling paramedics until saturation was reached. Interviews were recorded, transcribed verbatim, and coded through open, axial, and selective levels of coding, identifying the Basic Social Process (BSP) and developing a Grounded Theory. A second researcher (SH) independently reviewed early results, which were also member-checked with participants. RESULTS:Eleven paramedics were interviewed. The following six categories emerged: Context; Judgements and values; Isolation and system failure; Managing risk; Competence at the boundary of mental and physical health needs; Professional, legal and ethical tensions. The BSP Decision making in a context of risk was identified. The final Grounded Theory that emerged was one of 'Wicked Complexity of paramedic care for people who SH, which includes usual factors such as tiredness and frequent callers, heightened factors including lack of support and pathways, and factors specific to SH such assessing mental health and suicide risk. CONCLUSIONS:This study builds on a very small body of literature to have explored paramedic care for people who SH and has found that this care interaction provides uniquely complex challenges. The multiple influences within the categories defined in this study need considering conjointly when making improvements to care

Evaluating interventions to improve ethical decision making in clinical practice : a review of the literature and reflections on the challenges posed

Since the 1980s, there has been an increasing acknowledgement of the importance of recognising the ethical dimension of clinical decision-making. Medical professional regulatory authorities in some countries now include ethical knowledge and practice in their required competencies for undergraduate and post graduate medical training. Educational interventions and clinical ethics support services have been developed to support and improve ethical decision making in clinical practice, but research evaluating the effectiveness of these interventions has been limited. We undertook a systematic review of the published literature on measures or models of evaluation used to assess the impact of interventions to improve ethical decision making in clinical care. We identified a range of measures to evaluate educational interventions, and one tool used to evaluate a clinical ethics support intervention. Most measures did not evaluate the key impact of interest, that is the quality of ethical decision making in real-world clinical practice. We describe the results of our review and reflect on the challenges of assessing ethical decision making in clinical practice that face both developers of educational and support interventions and the regulatory organisations that set and assess competency standards

Spondylarthropathies (including psoriatic arthritis): 244. Validity of Colour Doppler and Spectral Doppler Ultrasound of Sacroilicac Joints Againts Physical Examination as Gold Standard

Background: Sacroiliac joints (SJ) involvement is a distinctive and charasteristic feature of Spondyloarthritis (SpA) and x-ray is the test routinely used to make a diagnosis. However, x-ray reveals late structural damage but cannot detect active inflammation. The objective of this study was to assess the validity of Doppler ultrasound in SJ. Methods: Prospective blinded and controlled study of SJ, in which three populations were compared. We studied 106 consecutive cases, who were divided into three groups: a) 53 patients diagnosed with SpA who had inflammatory lumbar and gluteal pain assessed by a rheumatologist; b) 26 patients diagnosed with SpA who didn't have SJ tenderness and had normal physical examination; c) control group of 27 subjects (healthy subjetcs or with mechanical lumbar pain). All patients included that were diagnosed with SpA met almost the European Spondyloarthropathy Study Group (ESSG) classification criteria. Physical examination of the SJ included: sacral sulcus tenderness, iliac gapping, iliac compression, midline sacral thrust test, Gaenslen's test, and Patrick s test were used as gold standard. Both SJ were examined with Doppler ultrasound (General Electric Logiq 9, Wauwatosa WI, USA) fitted with a 9-14 Mhz lineal probe. The ultrasonographer was blinded to clinical data. Doppler in SJ was assessed as positive when both Doppler colour and resistance index (RI) < 0.75 within the SJ area were present. Statistical analysis was performed estimating sensitivity and specificity against gold standard. The Kappa correlation coefficient was used for reliability study. Results: 106 cases (53 female, 55 male; mean age 36 10 years) were studied. There were no statistical differences between groups related to age or sex. Physical examination of SJ was positive in 38 patients (59 sacroiliac joints). US detected Doppler signal within SJ in 37 patients (58 SJ): 33 of them were symptomatic SpA (52 SJ), one of them were asymptomatic SpA (1 SJ) and one was a healthy control (1 SJ). The accuracy of US when compared to clinical data as gold standard at subject level in the overall group was: sensitivity of 68.6% and specificity of 85.7%, positive predictive value of 70.5% and negative predictive value of 84.5%. A positive likelihood ratio of 4.8, a negative likelihood ratio of 0.36 and a kappa coefficient of 0.55 were achieved. Conclusions: Doppler US of SJ seems to be a valid method to detect active SJ inflammation. Disclosure statement: The authors have declared no conflicts of interes

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Mortality in systemic lupus erythematosus in the United Kingdom 1999-2012

OBJECTIVES: To estimate the mortality associated with SLE during the period 1999-2012 by age, gender and region; and to ascertain the cause of death for people with SLE. METHODS: A retrospective cohort study using the UK Clinical Practice Research Datalink. Incident SLE cases diagnosed between 1999 and 2012 were matched by age, sex and practice to four controls. Age-, gender- and region-specific mortality rates were calculated per 1000 person-years and compared with control mortality rates using mortality rate ratios (MRRs). For individuals with linked Office of National Statistics data, cause of death was summarized by International Classification of Disease-10 chapter heading. RESULTS: Of 2740 incident cases, 227 died, giving a mortality rate of 15.84/1000 person-years (95% CI 13.91, 18.04). This was 67% higher than in controls (MRR 1.67, 95% CI 1.43, 1.94, P < 0.001). Men with SLE had higher rates of mortality than females with SLE. Compared with controls, the mortality rate for males with SLE was 1.80 times that of male controls (95% CI 1.32, 2.45, P < 0.001); for females the mortality rate was 1.64 times higher (95% CI 1.37, 1.96, P < 0.001). The age-specific mortality rates increased significantly with age; however, the MRR diminished from 3.81 (95% CI 1.43, 10.14) in those aged <40 years to 0.82 (95% CI 0.36, 1.83) in those 90 years. There was no significant difference in mortality between regions. Circulatory system disease and malignancy were the most frequent causes of death in both cases and controls. CONCLUSION: There remains an increased mortality for people with SLE compared with matched controls, particularly at younger ages

Practical Pharmacist-Led Interventions to Improve Antimicrobial Stewardship in Ghana, Tanzania, Uganda and Zambia.

The World Health Organisation (WHO) and others have identified, as a priority, the need to improve antimicrobial stewardship (AMS) interventions as part of the effort to tackle antimicrobial resistance (AMR). An international health partnership model, the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) programme, was established between selected countries in Africa (Ghana, Tanzania, Zambia and Uganda) and the UK to support AMS. This was funded by UK aid under the Fleming Fund and managed by the Commonwealth Pharmacists Association (CPA) and Tropical Health and Education Trust (THET). The primary aims were to develop local AMS teams and generate antimicrobial consumption surveillance data, quality improvement initiatives, infection prevention and control (IPC) and education/training to reduce AMR. Education and training were key components in achieving this, with pharmacists taking a lead role in developing and leading AMS interventions. Pharmacist-led interventions in Ghana improved access to national antimicrobial prescribing guidelines via the CwPAMS mobile app and improved compliance with policy from 18% to 70% initially for patients with pneumonia in one outpatient clinic. Capacity development on AMS and IPC were achieved in both Tanzania and Zambia, and a train-the-trainer model on the local production of alcohol hand rub in Uganda and Zambia. The model of pharmacy health partnerships has been identified as a model with great potential to be used in other low and middle income countries (LMICs) to support tackling AMR