bluuebunny/crossref_metadata_2025 huggingface dataset:
Diet complexity and l-threonine supplementation: effects on growth performance, immune response, intestinal barrier function, and microbial metabolites in nursery pigs
Authors: Koo Bonjin , Choi Janghan , Yang Chengbo , Nyachoti Charles Martin
Published: April 2020

The aim of this study was to investigate the effects of diet complexity and l-Thr supplementation level on the growth performance, immune response, intestinal barrier function, and microbial metabolites in nursery pigs. Thirty-two weaned pigs (body weight 7.23 ± 0.48 kg) were randomly assigned to dietary treatments in a 2 × 2 factorial arrangement based on diet complexity (complex or simple) and dietary Thr content. The complex diet contained fish meal, plasma protein, and dried whey to mimic a conventional nursery diet. The simple diet was formulated with corn, wheat, and soybean meal and did not contain any animal products. l-Thr was supplemented to each diet to supply either 100% (STD Thr) or 115% (SUP Thr) of the NRC (2012) requirement for standardized ileal digestible Thr. Pigs were individually housed and fed experimental diets ad libitum for 14 d. Diet complexity, dietary Thr content, and their interactions were considered the main effects. Pigs fed the simple diet had greater (P < 0.05) plasma interleukin (IL)-10 and IL-6 concentrations compared with those fed the complex diet on days 7 and 14, respectively. Simple diet-fed pigs tended to show greater (P < 0.10) expression of genes encoding for tumor necrosis factor-α, claudin-1, and zonula occludens-1 in the jejunum compared with complex diet-fed pigs. The simple diet-fed pigs had greater (P < 0.05) concentrations of NH3-N in the jejunum digesta than did complex diet-fed pigs. The SUP Thr increased (P < 0.05) villus height and goblet cell (GC) density in villi and crypts in the jejunum and deepened (P < 0.05) crypts in the proximal colon. The SUP Thr resulted in the upregulation (P < 0.05) of occludin gene expression and a tendency toward the downregulation (P = 0.10) of IL-6 gene expression in the jejunum. Interactions (P < 0.05) between diet complexity and l-Thr supplementation level were observed in GC density in the crypt, NH3-N concentration in the jejunum, and the contents of acetate, propionate, and total volatile fatty acids in the colon. In conclusion, feeding a simple diet to nursery pigs resulted in systemic and intestinal inflammation. The SUP Thr diet did not normalize the simple diet-induced inflammation but improved gut integrity. SUP Thr seems to have greater benefits with a simple diet than with a complex diet. Therefore, SUP Thr in a simple diet could be a beneficial nutritional strategy for enhancing gut health.
COVID-19 with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema
Authors: Wang Weiyi , Gao Rundi , Zheng Yulu , Jiang Libin
Published: April 2020

We present a case of COVID-19 pneumonia associated with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema.
Synchronous Teledermoscopy in Military Treatment Facilities
Authors: Day William G , Shrivastava Vikas , Roman John W
Published: April 2020

Sustained demand for dermatologic care throughout military medicine, in conjunction with increasing dermatologic provider shortages, has led to increase use of teledermatology in military treatment facilities (MTFs). Initially used to aid in the differentiation of suspicious melanocytic lesions, dermoscopy has found increasing clinical utility in an expanding realm of general dermatologic conditions. We demonstrate the use of synchronous teledermoscopy within a remote MTF by repurposing webcam technology already available at most MTFs. Two patients were seen in clinic at a remote naval primary care clinic with limited subspecialties. Once written consent was retrieved, an on-site dermatologist evaluated each patient and performed a history and skin exam with dermoscopy. Synchronous consultations were conducted with the Global Med Cart (GlobalMed(R) Clinical Access Station with TotalExam(R) 3 HDUSB camera), and Cisco webcam video jabber (Cisco TelePresence PrecisionHD USB Camera part number TTC8-03). The patients then underwent individual synchronous teledermatology consultations with an off-site U.S. Navy dermatologist located in the continental United States. The methodology for the consultation involved the use of a standard dermatoscope and jabber webcam. Two synchronous teledermatology consultations were completed successfully on patients in MTFs with limited subspecialty capabilities. Both cases, with two lesions of concern per case, had 100% concordance between the on-site and teleconsulted dermatologist. Through observing inter-rater agreements between the on-site and remote dermatologists, this small study demonstrates a novel application of technology readily available at most MTFs.
Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data
Authors: Delhomme Tiffany M , Avogbe Patrice H , Gabriel Aurélie A G , Alcala Nicolas , Leblay Noemie , Voegele Catherine , Vallée Maxime , Chopard Priscilia , Chabrier Amélie , Abedi-Ardekani Behnoush , Gaborieau Valérie , Holcatova Ivana , Janout Vladimir , Foretová Lenka , Milosavljevic Sasa , Zaridze David , Mukeriya Anush , Brambilla Elisabeth , Brennan Paul , Scelo Ghislaine , Fernandez-Cuesta Lynnette , Byrnes Graham , Calvez-Kelm Florence L , McKay James D , Foll Matthieu
Published: April 2020

The emergence of next-generation sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations, such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analysing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub platform: https://github.com/IARCbioinfo/needlestack.
Single-Cell Virtual Cytometer allows user-friendly and versatile analysis and visualization of multimodal single cell RNAseq datasets
Authors: Pont Frédéric , Tosolini Marie , Gao Qing , Perrier Marion , Madrid-Mencía Miguel , Huang Tse Shun , Neuvial Pierre , Ayyoub Maha , Nazor Kristopher , Fournié Jean-Jacques
Published: April 2020

The development of single-cell transcriptomic technologies yields large datasets comprising multimodal informations, such as transcriptomes and immunophenotypes. Despite the current explosion of methods for pre-processing and integrating multimodal single-cell data, there is currently no user-friendly software to display easily and simultaneously both immunophenotype and transcriptome-based UMAP/t-SNE plots from the pre-processed data. Here, we introduce Single-Cell Virtual Cytometer, an open-source software for flow cytometry-like visualization and exploration of pre-processed multi-omics single cell datasets. Using an original CITE-seq dataset of PBMC from an healthy donor, we illustrate its use for the integrated analysis of transcriptomes and epitopes of functional maturation in human peripheral T lymphocytes. So this free and open-source algorithm constitutes a unique resource for biologists seeking for a user-friendly analytic tool for multimodal single cell datasets.
A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01)
Authors: Balana Carmen , Vaz Maria Angeles , Manuel Sepúlveda Juan , Mesia Carlos , del Barco Sonia , Pineda Estela , Muñoz-Langa Jose , Estival Anna , de las Peñas Ramón , Fuster Jose , Gironés Regina , Navarro Luis Miguel , Gil-Gil Miguel , Alonso Miriam , Herrero Ana , Peralta Sergio , Olier Clara , Perez-Segura Pedro , Covela Maria , Martinez-García Maria , Berrocal Alfonso , Gallego Oscar , Luque Raquel , Perez-Martín Franciso Javier , Esteve Anna , Munne Nuria , Domenech Marta , Villa Salvador , Sanz Carolina , Carrato Cristina
Published: April 2020

Background

Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome.

Methods

Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948).

Results

From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001).

Conclusions

Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS.

Key Points

1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.

2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.

3. Extending adjuvant temozolomide was linked to increased toxicities.
EP01 Audit of the monitoring and documentation of DAS28 score in patients prescribed high cost DMARDs for rheumatoid arthritis every 6 months according to British Society for Rheumatology guidelines
Authors: Tsoi Kevin F. W , Sahni Amit , Selvanayagam Bianka , Memon Muhammad
Published: April 2020

Background

DAS28 is a measure of disease activity in rheumatoid arthritis (RA) which is comprised of the number of tender and swollen joints, inflammatory markers and visual analogue score. Both NICE and British Society of Rheumatology recommend DAS28 is recorded at least every 6 months in patients with RA, to monitor disease activity and ensure adequate response to treatment. CCG mandate 6 monthly DAS28 scores for patients on high cost DMARDs in order to secure funding. Absence of DAS28 scores results in CCGs refusing to fund treatment at the expense of the Trust.

Methods

Our aim was to review whether a DAS28 was documented in every consultation and if it meets the audit standard of a review every 6 months. If the 6 month target is not met, to understand the reason for this and to suggest ways to meet the standard. Blueteq is the software used to identify all patients with a diagnosis of RA between January 2014 and January 2019 at Royal Surrey County Hospital (RSCH). Clinic letters were reviewed to identify whether a DAS28 score was recorded, the date it was recorded and whether this was done within 6 months.

Results

In total, 207 patients are prescribed high cost DMARDs for RA at RSCH. 166 (80%) patients have a documented DAS28, but 41 (20%) patients did not have a documented DAS28. 14 (7%) patients have a documented DAS28 at least 6 monthly. 152 (73%) patients did not meet the audit standard.

Conclusion

Documentation of DAS28 in clinic letters at RSCH does not meet the audit standard. However, these scores have been recorded on Blueteq in order to satisfy CCG requirements. There needs to be consistency in where DAS28 is recorded. Factors contributing to an absence of a documented DAS28 in clinic letters include: no recent inflammatory markers, patients not receiving clinic appointments scheduled at the correct interval, patients not attending clinic, limited follow-up clinic capacity. DAS28 documentation can be improved by incorporating a table into each rheumatology clinic letter template. On initiation of a high cost therapy, the importance of regular blood monitoring and clinic attendance should be reiterated to patients as well as to the appointments booking team. An early arthritis pathway already exists, which can be extended to incorporate a high cost DMARD pathway detailing how to achieve target documentation.

Disclosures: K.F.W. Tsoi: None. A. Sahni: None. B. Selvanayagam: None. M. Memon: None.
EP04 Hypercalcaemia of sarcoidosis in a patient with severe renal impairment successfully treated with denosumab
Authors: Alshakh Randa , Gendi Nagui
Published: April 2020

Background

Denosumab has been used for the management of hypercalcaemia of malignancy where bisphosphonates are contraindicated (e.g. due to severe renal impairment). Unlike bisphosphonates, denosumab is not cleared by the kidneys. In one case report of a patient with multiple myeloma and severe renal impairment, denosumab therapy was associated with improvement in renal function. There are limited data for its use in the management of resorption related hypercalcaemia due to other causes including sarcoidosis.

Methods

We present the case of a 60 year old female with background chronic kidney disease (CKD), diabetes mellitus with severe retinopathy, non-alcoholic fatty liver disease, hypertension, and previous stroke. She was diagnosed with biopsy-proven sarcoidosis after she was admitted with hypercalcaemia of 3.7mmol/L. Her parathyroid hormone (PTH) was suppressed and total 25 vitamin D was low at 35 nmol/L. CT scan showed splenomegaly and multiple enlarged lymph nodes in the chest and abdomen. Lungs were clear. A CT guided para-aortic lymph node biopsy revealed non-caseating epithelioid granulomas with multinucleated giant cells. Her hypercalcaemia initially responded to intravenous hydration, high doses of oral and intravenous glucocorticoids, and pamidronate. Azathioprine was later started and the dose gradually titrated. However on reducing the dose of oral prednisolone, serum calcium started to rise reaching 2.9mmol/L in February 2019. Her eGFR was 22mL/min. Using FRAX, her 10 year probability of major osteoporotic and hip fracture was 13% and 1.1% respectively.

Results

The patient was given denosumab 60mg via subcutaneous route in March 2019 and her calcium has been normal since (see table). This is associated with improvement in renal function. Her PTH which was suppressed at presentation (0.7) was raised at 21.3 (normal range 1.3 - 9.3) pmol/L when last checked in September 2019, as would be expected in CKD. She is currently on 7mg of prednisolone and gradually weaning off. She remains on azathioprine 100mg BD.

Conclusion

We conclude that denosumab could be an option for the management of hypercalcaemia of sarcoidosis if bisphosphonates are contraindicated. More data are required to establish safety at variable degrees of renal impairment and to identify an optimal dose for this indication.

Disclosures

R. Alshakh None. N. Gendi None.
EP18 Use of anakinra for haemophagocytic lymphohistiocytosis in adults
Authors: Sammut Luke , Murryam Saerrah , Vincent Natalie , Davidson Brian , Edwards Christopher J
Published: April 2020

Background

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening syndrome characterised by severe immune activation. The primary form occurs in early childhood and is fatal without treatment. Secondary HLH can occur at any age, usually in the setting of autoimmune disease, malignancy and infections. Macrophage activation syndrome is a form of HLH occurring in patients with juvenile idiopathic arthritis or other rheumatological conditions. The 2004 paediatric HLH treatment protocol is an established regime of etoposide, dexamethasone and ciclosporin. In recent years, studies have suggested a role for Anakinra in paediatric patients with HLH. We describe our recent experience with Anakinra in adult patients with secondary HLH.

Methods

We performed a retrospective case review study of four adults diagnosed with HLH and treated with anakinra between 2014 and 2018.

Results

Three males and one female with mean age of 35 (18-53) fulfilled the 2004 HLH diagnostic criteria. Three patients had confirmed secondary HLH with the primary trigger being CMV infection, a connective tissue disease (CTD) & T-cell lymphoma and adult-onset Still’s disease. The aetiology of the fourth patient was uncertain although viral infection was likely. Common presenting features were fever, hyperferritinaemia and anaemia. Three patients were neutropaenic and two pancytopaenic. The peak mean ferritin level was 50358µg/L, (10052 - 126808). All patients were treated with anakinra 100mg subcutaneously per day. Ferritin fell rapidly, and at day 7 following treatment, the mean was 3688µg/L (645 - 8957). Three patients achieved initial clinical remission. The first stopped anakinra after 14 days of treatment and has done well, the second has remained on treatment. The third achieved initial clinical remission, stopped anakinra after two months but relapsed and died from atypical pneumonia. The fourth with CTD and T-cell lymphoma had a large drop in ferritin but did not achieve remission and died (Table 1).

Conclusion

HLH is a rare life threatening disorder. Similar to paediatric studies, anakinra appears to reduce ferritin rapidly in adults with secondary HLH. Anakinra may be effective in improving the clinical outcome in adults with non-malignancy associated secondary HLH. However, consistent with previous reports, patients with malignancy associated HLH had a worse survival.

Disclosures

L. Sammut None. S. Murryam None. N. Vincent None. B. Davidson None. C.J. Edwards Honoraria; C.J.E has received support to attend meetings and received honoraria from Amgen.
EP20 Long term safety and efficacy of denosumab and zoledronate
Authors: Alkutobi Ziad , Laila Deena , Tariq Mohammad
Published: April 2020

Background

Denosumab and zoledronate are increasingly prescribed for primary and secondary osteoporosis long-term management.

Methods

A retrospective audit was conducted at Basildon Hospital during 2012-2019 using the NICE guidelines standards to evaluate the long term safety and efficacy of denosumab and zoledronate. Number of patients was 84, diagnosed with osteoporosis or osteopenia, 34 of them received 10 or more denosumab injections and 50 patients planned to receive 5 zoledronate infusions (9 patients received 5 and 38 patients received 4).

Results

Forty percent of the patients were at their 8th decade followed by 28.57% and 21.42 % at their 9th and 7th decades respectively. More than 90% were Caucasian females. Primary prevention was in 39.28% and secondary prevention in 60.71%. The commonest sites of fracture were the wrist and vertebrae at 34.37% for each; followed by the neck of femur and humerous at 12.5% for each. Denosumab was the 1st, 2nd, 3rd or 4th line of treatment in 9.52%, 13.09%, 16.66% and 1.19% respectively; whereas zoledronate was the 1st, 2nd or 3rd line of treatment in 13.09%, 40.47% and 5.95% respectively. The commonest reason for choosing denosumab as the first line was chronic kidney disease, whereas the reason for choosing it as the 2nd or 3rd line was inefficacy of bisphosphonate in 69% or gastrointestinal side effects in 14%. Zoledronate was chosen in all cases because of intolerability to oral bisphosphonate or gastrointestinal side effects. Repeat DXA scan was performed after the 5th, 10th denosumab injections and the 3rd zoledronate infusions. After the 5th Denosumab, DXA scan showed improvement or stability in 100% and 85.29% at the spine and hip respectively whilst deterioration was seen in 14.7% at the hip. After the 10th denosumab, the rate of improvement or stability at the spine was reduced to 88.23% and decline was seen in 2.94%. At the hip area, 73.52% continued to show improvement or stability, whilst 17.66 % showed deterioration. After the 3rd zoledronate, 98% and 88% showed improvement or stability at the spine and hip respectively whilst deterioration seen in 2% and 12% at the spine and hip respectively. One patient on zoledronate experienced dental issues after the 4th injection and stopped treatment. There were no jaw osteonecrosis, no new fractures and no significant side effects with either denosumab or zoledronate. Ninety percent of patients who completed 10 denosumab injections were planned to continue for another 5 injections.

Conclusion

After the period of 3-5 years, denosumab and zoledronate were well tolerated and BMD was either stable or improved at both spinal and hip sites. There were few cases of deterioration mainly at the hip area with both zoledronate and denosumab. Future researches are needed to stratify guidelines on discontinuation of denosumab.

Disclosures

Z. Alkutobi None. D. Laila None. M. Tariq None. A. Nandagudi None.
EP21 An observational study of the predictors of osteoporosis in men
Authors: Kyrtata Natalia , Davies Kristen , Nune Arvind , Bukhari Marwan
Published: April 2020

Background

Osteoporosis is under-recognised and under-treated in men. Previous studies and stratification tools have been limited in their generalisability and while predictors of poor bone density in men have been characterised, evidence has been contradictory. The purpose of this study is to investigate these predictors in the lumbar spine and femoral neck in men.

Methods

Data were collected from 3,901 men referred for DEXA scanning to the Royal Lancaster Infirmary, between 2004 and 2010. BMD was measured in the lumbar spine and femoral neck. Simple and multiple regression models were fitted to each measurement site, using each of the known predictors for poor bone health. The Variance Inflation Factor was used to quantify the severity of multicollinearity and the Akaike Information Criterion was employed to select co-variates.

Results

The following predictors had a significant effect in both measurement sites: age; height; weight; Body Mass Index (BMI); X-ray evidence of osteopenia; and previous fracture(s). Body fat percentage had a significant effect at the lumbar spine only, and tobacco use had a significant effect at the femoral neck only. The adjusted R squared values for the models ranged from 0.16 for the lumbar spine model, to 0.28 for the femoral neck model.

Conclusion

This study demonstrated that further work is needed in assessing the predictors of OP in men. This would open up an interesting observation in clinical practice and provide an opportunity for risk prediction and primary prevention of OP in men, reducing fracture risk. Future studies should include randomised samples and propensity score matching.

Disclosures

N. Kyrtata None. K. Davies None. A. Nune None. M. Bukhari None.
EP23 Subcutaneous methotrexate from the get-go: better adherence and tolerability
Authors: Bevington Catherine , Achilleos Katerina , Smith Jessica , Smith Victoria
Published: April 2020

Background

Several studies have shown subcutaneous methotrexate (s/c MTX) to be superior to oral for treatment of rheumatoid arthritis. However s/c MTX is rarely started first line.

Methods

We audited the first 67 patients started on s/c MTX at diagnosis and compared to a previous cohort of treat-to-target patients started on oral MTX.

Results

There was a significant difference in adherence: for every 1 patient staying on oral, 1.5 patients stayed on s/c MTX. There was no difference in final numbers in remission, escalation to biologics, or time to remission. Nearly half the patients on oral MTX had switched to s/c at 1 year, either for side effects or inefficacy.

Conclusion

Adherence to s/c MTX was better than adherence to oral MTX in our study. The large number of switches from oral to s/c suggests that adherence is improved due to improved tolerability and reduced side effects of s/c MTX.

Disclosures

C. Bevington None. K. Achilleos None. J. Smith Grants/research support; JS received £500 from Medac to carry out the audit. V. Smith: None.
EP28 Adenosine deaminase-genetic polymorphism and baseline serum level as a biomarker of treatment response to methotrexate in rheumatoid arthritis
Authors: Nair Harikrishnan Gangadharan , Singh Ankita , Majumder Sanjukta , Aggarwal Amita
Published: April 2020

Background

Despite methotrexate (MTX) being the first line therapy for RA,30% of patients do not respond to MTX. Methotrexate acts by increasing adenosine levels which lead to anti-inflammatory effects. Adenosine deaminase (ADA) enzyme converts adenosine to inosine thus reduces levels of adenosine. Thus, ADA levels and single nucleotide polymorphism (SNP) in ADA gene may affect the treatment effect of MTX. Our objective was to study if genetic polymorphism in ADA gene and baseline serum ADA levels in patients with RA is associated with methotrexate response.

Methods

207 DMARD naïve active RA (DAS28 ESR ≥3.2) patients satisfying EULAR/ACR 2010 criteria were enrolled. Genotyping was done in all patients (n = 207) by TaqMan 5' nuclease assay. In a subset of patients(n = 59) blood sample was collected at baseline and 2 months for ADA estimation by ELISA. Ethical approval and written informed consent was taken. Oral MTX was initiated at dose of 15mg/week, escalated 5mg every month till the patients had DAS28 < 2.6 or a maximum dose of 25 mg/week was reached. At 4 months based on EULAR response patients were classified as responders or non-responders. Using a Chi-squared test, SNPs were associated with response to methotrexate therapy. Baseline clinical parameters and serum ADA levels were correlated with EULAR response.

Results

Among 207 patients (177females) mean age was 41.49± 12.14 years and median disease duration 24 (40) months.172 patients (83.1%) were responders and 35 (16.9%) non-responders. 197 (95.16%) patients were seropositive (RF and/or ACCP+). With regard to SNP in ADA gene,47.8% were AA,42.5% AG and 9.7% were GG genotype. Mean DAS 28 CRP was 4.76 ± 1.05 and median DAS 28 ESR was 6.00 (1.38). Mean serum baseline ADA was 10.82 ±5.33 pg/dl. Except DAS28ESR (p = 0.02), other baseline parameters like age, disease duration, ESR, CRP, DAS 28 CRP were similar between responders and non-responders. SNPs in ADA gene were not associated with EULAR response (p = 0.475). Baseline ADA levels (10.52 ± 5.37 vs 12.28 ± 5.14; p = 0.34) 2 month ADA levels (p = 0.34) and change in ADA level from baseline at 2 months, i.e. delta ADA (p = 0.55) did not show any association with MTX response. Mean ADA level was similar between the 3 genotypes of ADA(p = 0.736) Comparison of parameters between methotrexate responders and non-responders

Conclusion

ADA gene polymorphism and serum ADA levels do not affect response to methotrexate.

Disclosures

H. Gangadharan Nair: Grants/research support; Indian Rheumatology Association Research grant. A. Singh: None. S. Majumder None. A. Aggarwal None.
EP36 Vitamin D and interferon signature gene expression in systemic lupus erythematosus: a cross-sectional cohort study
Authors: Magro Rosalie , Saliba Christian , Camilleri Liberato , Scerri Christian , Borg Andrew A
Published: April 2020

Background

Vitamin D deficiency is more prevalent in patients with systemic lupus eythematosus (SLE) as a result of sun avoidance. The potential negative impact of vitamin D deficiency on the disease activity of SLE has been shown in a number of studies. The expression of the interferon signature genes in SLE correlates positively with disease activity, and these genes are thought to mediate the clinical manifestations of the disease. The aim of this study was to establish whether a relationship exists between serum 25-hydroxyvitamin D level and the interferon signature gene expression in whole blood of SLE patients.

Methods

Informed consent was obtained from 92 SLE patients who were over the age of 18 and who fulfilled the SLICC classification criteria for SLE. The patients were interviewed and blood tests including full blood count, renal profile, calcium, 25-hydroxyvitamin D, complement 3 (C3), complement 4 (C4) and anti-double standed DNA (anti-dsDNA) titre were carried out. SLE disease activity was measured by SLE disease activity index-2K (SLEDAI-2K). RNA extraction was performed from whole blood. QuantiGene Plex technology was used to measure the expression of 12 interferon signature genes in the extracted RNA. The study was approved by the University Research Ethics Committee.

Results

92.4% of the cohort studied were female. 58.7% were receiving vitamin D3 supplementation at a mean dose of 1031IU daily. 27.2% had vitamin D insufficiency (25-hydroxyvitamin D 21-29ng/ml) and 15.2% were vitamin D deficient (25-hydroxyvitamin D < 20ng/ml). Mean serum 25-hydroxyvitamin D was 30.75ng/ml (standard deviation 9.53 ng/ml). Median SLEDAI-2K was 4 (range 0-12). Serum 25-hydroxyvitamin D had a significant negative correlation with body mass index (BMI) (R=-0.258, p = 0.006) but there was no significant negative correlation with SLEDAI-2K or with the expression of the interferon signature genes. The expression of most interferon signatures genes measured (IFI35, OAS1, MX1, IFITM1, STAT2, IFIT3, IFIT1, STAT1, SOCS1) had a significant positive correlation with SLEDAI-2K.

Conclusion

This study did not show a significant relationship between serum vitamin D level and disease activity. In keeping with this, there was no significant negative correlation between serum 25-hydroxyvitamin D and interferon signature gene expression. Further prospective studies and randomised controlled trials are required to study this relationship in greater depth.

Disclosures

R. Magro None. C. Saliba None. L. Camilleri None. C. Scerri None. A.A. Borg None.
EP40 Real world efficacy of secukinumab: a single centre experience
Authors: Blake Tim , Gullick Nicola J
Published: April 2020

Background

Secukinumab was approved by NICE for patients with active ankylosing spondylitis and psoriatic arthritis in 2017. Clinical trial data suggests secukinumab is a useful treatment option in both conditions, but often real world experience differs greatly from clinical trial results. In addition, patients with more refractory disease are often excluded from clinical trials.

Methods

Patients starting secukinumab at UHCW were identified from the Blueteq funding database. Medical notes were reviewed retrospectively to assess response rates using BASDAI responses in Ankylosing spondylitis and PsARC responses in PsA. Patients who had previously had inadequate response to TNF inhibitors (PsA only) and severe psoriasis received 300mg secukinumab monthly; the remainder were prescribed 150mg monthly.

Results

113 patients commenced secukinumab between June 2017 and April 2019 and had outcome data recorded. 59 patients (52%) had received previous biologic agents prior to secukinumab exposure. Patients with ankylosing spondylitis had high BASDAI (6.91.4) and spinal pain (7.71.4). 38 patients had an initial response to treatment. Secukinumab was effective in 39 patients (63%), and 37 (62%) continued treatment. In psoriatic arthritis, despite high levels of activity at baseline (mean tender joint count 10 8; swollen joint count 63, and 65% prior biologic exposure, high rates of response were seen. The majority of patients have continued treatment. Secukinumab was well tolerated in both patient groups with low rates of discontinuation due to adverse events (11 patients, 9%). Adverse events included recurrent infection (6), rash (1), mouth ulcers (1), vertigo (1), new onset cancer (1) and new onset Crohn’s (1) although rates were low overall. Patients with pre-existing uveitis did not develop exacerbations but low numbers of patients with prior uveitis were treated.

Conclusion

Secukinumab demonstrates high levels of efficacy even in a cohort of patients with longstanding PSA and AS with high rates of inadequate responses to other biologics. Secukinumab is well tolerated with low rates of discontinuation due to adverse events.

Disclosures: T. Blake: None. N.J. Gullick: Honoraria; NG has received Honoraria from Abbvie, Eli Lilly, Novartis, UCB. Grants/research support; NG has received funding for research from Abbvie and Novartis.
O18 National variation and factors associated with long-term opioid use for non-cancer pain in the first year of use
Authors: Jani Meghna , Birlie-Yimer Belay , Sheppard Therese , Lunt Mark , Dixon William G
Published: April 2020

Background

Physician prescribing behaviour has been described as a key driver of rising opioid prescriptions and long-term opioid use. However, the effect of prescribers requires interpretation within context. No studies have investigated the extent to which regions, practices, prescribers, vary in opioid prescribing by considering this hierarchy together, whilst accounting for case-mix. Objectives: (i)quantify and identify risk factors for the transition from new-users to long-term opioid users (ii) quantify variation of long-term use attributed to region, practice, prescriber, accounting for patient mix and chance variation.

Methods

We conducted a retrospective observational study between 2006-2017 using Clinical Practice Research Datalink. New users of opioids, ≥18 years, without cancer were identified. Long-term opioid use was defined as ≥ 3 opioid prescriptions within a 90-day period from index date, or ≥ 1 opioid prescription lasting at least 90-days in the first year. A multi-level random-effects logistic regression model was used to examine the association of patient characteristics with the odds of becoming a long-term opioid-user. To examine variation in opioid use among prescribers, GP-practices and region after adjusting for case-mix, we used a nested random-effect structure. A ‘high-risk’ region, prescriber or practice was defined as those where the entire adjusted 95% CI lay above population average.

Results

1,968,742 new opioid users were included; 14.6% transitioned to long-term use. In the fully-adjusted model, factors associated with higher-odds of long-term use included high morphine-milligram equivalents (MME)/day at first prescription, older-age, deprivation, fibromyalgia, rheumatological conditions and prior surgery (Table 1). After adjustment for case-mix, the North-West, Yorkshire and South-West were found to be high-risk regions for long-term use. 103 practices (25.6%) and 540 prescribers (3.5%) were associated with a significantly higher risk of long-term use. The odds of becoming a long-term user for patients belonging to these prescribers reached up to > 3.5 times than the population average.

Conclusion

Prescribing factors, age, deprivation and conditions including fibromyalgia and rheumatological conditions were associated with higher odds of long-term opioid use. In the first UK study evaluating long-term opioid prescribing with patient-level characteristics adjustment, variation in regions, especially practices and prescribers were observed. Our findings support greater calls for action to reduce practice/prescriber variation by promoting safe practice in opioid-prescribing.

Disclosures

M. Jani: None. B. Birlie-Yimer: None. T. Sheppard: None. M. Lunt: None. W.G. Dixon: None.
O29 Methotrexate response clusters in JIA
Authors: Shoop-Worrall Stephanie J. W , Hyrich Kimme L , Wedderburn Lucy R , Thomson Wendy , Geifman Nophar ,   CLUSTER, BSPAR-ETN, BCRD
Published: April 2020

Background

Treatment response in juvenile idiopathic arthritis (JIA) is currently viewed as a binary outcome of response versus non-response. In a heterogenous disease such as JIA, it is likely that different, identifiable clusters of children and young people (CYP) may display varying patterns of the different features of the disease. Identifying these response clusters is an important step toward stratified medicine in JIA. The aim of the study was to explore trajectories of juvenile arthritis disease activity score (JADAS) components following methotrexate (MTX) initiation for JIA.

Methods

MTX-naïve CYP with JIA were selected if enrolled prior to January 2018 in either the UK BSPAR Etanercept Register or the Biologics for Children with Rheumatic Diseases Study at point of starting MTX. JADAS components (active joint count, physician’s global assessment (0-10cm), parental global evaluation (0-10cm) and standardised ESR (0-10) were calculated based on data collected in the year following MTX initiation. Multivariate group-based trajectory models were used to explore MTX response clusters across the different JADAS components, using censored-normal (global scores, ESR) and zero-inflated Poisson (active joint count) models. Optimal models were selected based on a combination of model fit (BIC), parsimony and clinical plausibility.

Results

Of 611 CYP selected, the majority were female (69%) and of white ethnicity (85%), with RF-negative JIA the most common disease category (33%). The optimal model identified multiple patterns of disease activity following initiation of MTX, which have greater complexity than simple ‘response’ versus ‘non-response’ clusters. Differences between clusters included initial intensity of disease features and speeds of improvement over time. In addition, the components of the JADAS did not always follow similar patterns over time, even within the same outcome cluster.

Conclusion

This study has identified that within CYP initiating MTX, different patterns of disease activity are apparent, suggesting that a simple responder/non-responder analysis at a set point may be inadequate. Understanding both clinical factors associated with, and biological mechanisms underpinning, these clusters would aid stratified medicine in JIA.

Disclosures

S.J.W. Shoop-Worrall None. K.L. Hyrich None. L.R. Wedderburn None. W. Thomson None. N. Geifman None.
O30 Long non-coding RNA HOTAIR induces beta catenin expression in systemic sclerosis through EZH2 dependent repression of Axin-2
Authors: Wasson Christopher W , Abignano Giuseppina , Ross Rebecca , Galdo Francesco Del
Published: April 2020

Background

Fibroblasts explanted from affected tissues in systemic sclerosis (SSc) maintain their pro-fibrotic phenotype in vitro. This includes increased secretion of collagens and other extracellular matrix proteins and increased proportion of α-Smooth Muscle Actin (α-SMA) positive cells (myofibroblasts). It has been previously shown that among their profibrotic features, myofibroblasts display activation of WNT signalling, which is linked to a decreased basal expression of AXIN2. Here we aimed to determine whether specific long non-coding RNA (lncRNAs) expressed in myofibroblasts could drive the epigenetically stable decreased expression of Axin 2 in vitro.

Methods

Full thickness skin biopsies were surgically obtained from the forearms of twelve adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted from the fibroblast cultures. Laser capture was performed to isolate cells expressing or not α-SMA as a marker of myofibroblast differentiation. LncRNA HOTAIR was overexpressed in healthy dermal fibroblasts by lentiviral induction. EZH2 was blocked in cultured fibroblasts with the specific inhibitor GSK126.

Results

HOTAIR expression was increased in SSc patients’ skin (100 fold) and in SSc explanted fibroblasts (5 fold; p < 0.001 for both). Further, laser captured α-SMA expressing fibroblasts expressed in average 2.5 fold higher HOTAIR RNA levels compared to α -SMA negative cells from the same donors (P < 0.05). In vitro, lentiviral induced stable overexpression of HOTAIR in healthy dermal fibroblasts led to their profibrotic activation, including significantly increased expression of Col1A1 and α-SMA both at mRNA and protein levels (2.8 and 1.8 fold respectively, p < 0.05). We further showed that HOTAIR-induced profibrotic activation was due to EZH2 dependent spread of H3k27me3 methylation marker, as demonstrated by complete inhibition by treatment with GSK126. HOTAIR driven EZH2 histone methylation suppressed the expression of Axin 2 in SSc fibroblasts. The reduced Axin 2 levels led to stabilisation of beta catenin and WNT signalling pathway activation.

Conclusion

Here we show that the epigenetically stable activation of SSc dermal fibroblasts is due to HOTAIR. We also identified a major downstream target of HOTAIR is Axin-2. The results of these studies identify a new venue to modulate fibroblasts biology which could inform clinical research to resolve chronic fibrosis and re-establish tissue homeostasis in SSc.

Disclosures

C.W. Wasson None. G. Abignano None. R. Ross None. F. Del Galdo Consultancies; AstraZeneca, GSK, Boehringer-Ingelheim, Actelion, Capella Biosciences, Chemomab.
O38 The relationship between obesity and outcomes in patients with polymyalgia rheumatica
Authors: Scott Ian C , Bajpai Ram , Hider Samantha L , Helliwell Toby , Muller Sara , Mallen Christian D
Published: April 2020

Background

Obesity predisposes to a pro-inflammatory state. Studies have reported worse clinical outcomes in patients with inflammatory arthritis who are obese. The relationship between obesity and outcomes in patients with polymyalgia rheumatica (PMR), another common inflammatory rheumatic condition, has not been assessed. We examined this in a cohort study of primary care-recruited patients with PMR.

Methods

The PMR Cohort Study is an inception cohort of patients with incident PMR, recruited from 382 general practices. Self-completed questionnaires at 0, 12, and 24-months captured: (a) PMR-related pain (0-10 numeric rating scale [NRS]); (b) PMR-related stiffness (0-10 NRS); (c) anxiety (GAD7); (d) depression (PHQ8); (e) fatigue (FACIT-Fatigue); (f) function (mHAQ); (g) quality of life (EQ-5D-3L). Height was self-reported at baseline, and weight at baseline, 12 and 24 months. Patients were categorised as underweight (BMI<18.5 kg/m2); normal weight (18.50-24.99 kg/m2); overweight (25-29.99 kg/m2); or obese (≥30 kg/m2). Piecewise, multivariable, multilevel, linear mixed-effects regression models examined relationships between BMI categories and outcomes over time, using restricted cubic spline functions. Adjustments were made for age, sex, prednisolone-use, smoking, and alcohol. Due to few underweight patients (three at 0 months; one at 12/24 months), underweight and normal weight patients were combined, as a single reference group.

Results

652 patients were included (62% female). At baseline, mean age was 72 years, median BMI 26.6 (IQR 24.0-30.2), 34% were normal/under-weight, 40% overweight, and 26% obese. Compared to normal/underweight patients, obese patients had the following significantly poorer outcomes (P<0.05): higher pain scores at 12-months; higher stiffness scores at 12 and 24 months; higher depression levels at 12 and 24 months; worse fatigue at 0, 12 and 24 months; worse function at 12 and 24 months; worse quality of life at 0, and 12 months. BMI changed little over 24 months (25.7% and 25.9% obese at 0 and 24-months, respectively).

Conclusion

Obesity is associated with poorer outcomes in patients with PMR. Consideration should be given to providing weight management support to patients with PMR and obesity. Further research should examine the impacts of weight-based steroid dosing on outcomes.

Disclosures

I.C. Scott None. R. Bajpai None. S.L. Hider None. T. Helliwell None. S. Muller None. C.D. Mallen None.
P01 Hydroxychloroquine retinopathy: is screening necessary?
Authors: Gobbett Anne , Smith Jonathan , Bracewel Claire
Published: April 2020

Background

Hydroxychloroquine (HCQ) has long been associated with a low prevalence (0.5%) of retinal toxicity with possible irreversible sight loss. New retinal imaging techniques have suggested a significantly increased prevalence of HCQ retinopathy (7.5%). In light of this result, the American Academy of Ophthalmology (AAO) in 2016 and subsequently the Royal College of Ophthalmologists (RCO) in 2018 produced new screening guidelines. We report the HCQ retinopathy screening results for all patients referred to our Ophthalmology department from 1/11/2017 to date.

Methods

We collected prospective data from all patients referred for HCQ screening. Patients were screened according to the new RCO guidelines. We recorded each patient's dose and duration of HCQ treatment, their weight and renal function, and concurrent use of tamoxifen to determine their risk factors. Retinal images: colour fundal photos, ocular coherence tomography (OCT) and auto-fluorescence (AF), were performed on all patients (baseline tests), and visual acuity, automated central visual field testing (Humphrey 10:2) and multi focal electroretinography (mfERG) performed as indicated for those at risk, needing annual testing.

Results

We have diagnosed two definite cases of hydroxychloroquine retinopathy, giving us a prevalence of 2/639 (0.31%) of all screened, and 2/308 (0.64%) of those considered to be at risk according to RCO guidelines. 711 patients have been referred to our screening service so far. 639 of these have been screened with 72 failing to attend. 308 of all those screened have been categorised to be at increased risk of retinopathy: duration of treatment >5 years (224), dose > 5mg/kg/day (40), eGFR< 60ml/min/1.73m2 (111) and use of tamoxifen (0). 64 have multiple risk factors. 119 of those screened have completed their second cycle of screening, with 48 patients failing to attend for this repeat screening.

Conclusion

Our results for HCQ retinopathy screening suggest a prevalence more in keeping with the originally proposed figure than that in the recent literature; this may be multifactorial. We have a smaller number of patients, with fewer of those patients in the higher risk categories than in the study that prompted the change in screening guidelines. We only have baseline or two years of serial images for each patient at present, the comparison of multiple serial images may highlight more cases of retinopathy. More data is needed before we can suggest our figures are statistically different.

Disclosures

A. Gobbett None. J. Smith None. C. Bracewell None.