bluuebunny/crossref_metadata_2025 huggingface dataset:
EP19 Hyperferritinaemia causes in a UK district general hospital
Authors: Fieldman Tom , Stimson Laura , Zeb Shabeena , Alderson Steven , Lloyd Mark
Published: April 2020

Background

Hyperferritinaemia has multiple causes including iron overload, liver disease, and systemic inflammation either in the context of infection, autoimmunity, or malignancy. Marked hyperferritinaemia has been used to aid diagnosis of rare autoimmune conditions such as adult onset Still’s disease.

Methods

Patients with plasma ferritin concentrations over 3000 μg/L from 7 April 2014 until 30 August 2019 (just over 5 years) in a district general hospital were identified. Those without sufficient documentation to identify the likely causes of hyperferritinaemia were excluded. Included patients (n = 283) were grouped according to maximum ferritin concentration, and likely causes of hyperferritinaemia from the following list were classified as follows: Infection; solid organ malignancy; haematological malignancy, autoimmune disease; transfusion dependence; liver disease, renal failure, haemolytic anaemia.

Results

The most common causes of hyperferritinaemia were infection (31%), solid organ malignancy, (28%), haematological malignancy (23%), and liver disease (22%). Peak ferritin concentration did not appear to be strongly associated with the factors that caused it. To explore the diagnostic utility of ferritin to distinguish autoimmune processes, infection, malignancy, and liver disease, an association between these factors and maximum ferritin concentration was tested for using Fisher’s exact test. No statistically significant association was found (p = 0.8967).

Conclusion

We found no association between maximum ferritin concentration and the causes thereof, however this study does not elucidate the diagnostic utility of hyperferritinaemia since most of the patients studied had established diagnoses before their hyperferritinaemia was identified. Hyperferritinaemia appears to be a marker of severe disease, in that most of the patients studied had died by the time of data collection.

Disclosures

T. Fieldman None. L. Stimson None. S. Zeb None. S. Alderson None. M. Lloyd None.
EP26 Do early synovitis clinics triage patients with RA affectively?
Authors: Cleaton Natasha , Khan Tahir , Raizada Sabrina R
Published: April 2020

Background

In 2013, the UK National Institute for Health and Care Excellence (NICE) published quality standards for the treatment of rheumatoid arthritis (RA); emphasising the importance of early diagnosis and treatment of RA and these were updated in 2018. NICE quality statement 1 recommends that patients with a suspected inflammatory arthritis are referred to a rheumatology service within 3 working days of presentation. Quality statement 2 recommends that these patients are assessed in a rheumatology service within 3 weeks of referral. In view of these quality standards and the benefit of treating patients with RA, early Early Synovitis Clinics (ESC) were set up at the Royal Wolverhampton Trust (RWT). GPs were invited to refer patients electronically to the ESC if they had a swollen joint, positive antibodies (RhF or anti CCP) and if they suspected RA. All referrals to the ESC and all other new patient referrals were triaged by a consultant rheumatologist to determine if they were suitable for the ESC.

Methods

This is a retrospective service evaluation based on new patients seen in the ESC at the RWT over a 12month period, January to December 2018. The electronic records of patients seen in the ESC were retrospectively accessed and data was collected including gender, age and diagnosis.

Results

284 new patients attended the ESC in 2018; 186 (65.49%) were female, 98 (34.51%) were male. The patients age ranged 18-95years with a mean age of 58.75. 72 patients (25.4%) were classified as having RA. 135 patients (47.54%) were classified as having inflammatory arthritis, diagnoses within the inflammatory arthritis group were: psoriatic arthritis, crystal arthritis, Palindromic rheumatism, polymyalgia rheumatica, Reactive arthritis and undifferentiated inflammatory arthritis. 84 patients (29.58%) patients received a diagnosis of osteoarthritis, 12 patients (4.22%) were classified as having a connective tissue disease, 44 (15.49%) of the 284 patients were diagnosed with a condition classified in the category of soft tissue rheumatism.

Conclusion

This analysis found while 47.54% of patients referred to the ESC at RWT received a diagnosis categorised as inflammatory arthritis, only 25.4% of patients had RA. This compares to the recent National Early Inflammatory arthritis audit where only 35% of patients seen in rheumatology clinics with suspected inflammatory arthritis had a subsequent confirmed diagnosis of an inflammatory arthritis. This suggests more guidance needs to be provided to primary care services regarding the indications for referral to the ESC in order to provide appropriate capacity for patients with RA to be reviewed and treated quickly.

Disclosures

N. Cleaton: None. T. Khan: None. S.R. Raizada: None.
O27 Early experience with JAK inhibitor prescribing in the UK: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA)
Authors: Kearsley-Fleet Lianne , Davies Rebecca , Watson Kath , Lunt Mark , Hyrich Kimme L ,   the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA)
Published: April 2020

Background

In 2017, a new class of oral disease modifying anti-rheumatic drugs (DMARDs), janus kinase inhibitors (JAKi), were licensed for rheumatoid arthritis (RA): baricitinib and tofacitinib. In the UK, they are approved for use in patients with high disease activity with or without methotrexate, following failure of conventional synthetic (cs) DMARDs or biologic DMARDs, the latter when rituximab is contraindicated. As a new therapy option, it is currently unclear how and when these drugs are being prescribed in patients with RA. This analysis aims to describe the characteristics of patients starting JAKi and registered with the BSRBR-RA.

Methods

The BSRBR-RA aims to capture exposure and outcome data in patients with RA receiving biologics, biosimilars and targeted synthetic DMARDs. At the start of therapy, demographic and clinical data, including past treatment data, are collected. Characteristics of all patients receiving a JAKi for the first time with data recorded in the BSRBR-RA up to 31/03/2019 are described.

Results

To 31/03/2019, 698 patients in the BSRBR-RA have been treated with a JAKi; 596 patients baricitinib and 110 tofacitinib (Table 1). A quarter of patients received a JAKi with no prior biologic exposure; 148 (25%) baricitinib and 16 (15%) tofacitinib. Of these, 15% had a prior malignancy history. Of those with prior biologic exposure, the median number of previous biologics was 3 (IQR 2-4), the majority had prior TNFi (91%) or rituximab (51%), and 50% were receiving concurrent methotrexate.

Conclusion

To date, more patients have been recruited starting baricitinib than tofacitinib, likely owing to the later licensing of tofacitinib. Two groups are emerging with a quarter of patients receiving JAKi immediately after csDMARDs and a majority as a later stage alternative following multiple biologics. Further recruitment and follow-up patients will allow for analysis of real-world safety and effectiveness, but differences in patient characteristics will need to be considered in any comparative effectiveness analyses.

Disclosures

L. Kearsley-Fleet None. R. Davies None. K. Watson None. M. Lunt None. K.L. Hyrich Honoraria; AbbVie. Grants/research support; UCB, Pfizer, BMS.
O40 Trends in incidence of GCA in the UK
Authors: Barnett Lauren A , Helliwell Toby , Jordan Kelvin , Prior James
Published: April 2020

Background

Giant cell arteritis (GCA) is the most common form of medium and large vessel vasculitis. Diagnosis remains difficult since there are a multitude of symptoms experienced by patients with GCA and if not promptly identified or treated, patients with GCA are at risk of irreversible visual loss. Therefore, a clear understanding of recent trends in incidence is important for clinicians, researchers and policy-holders to better understand and address future healthcare resource needs. Our objective was to estimate the annual UK incidence of GCA and assess whether this is changing over time.

Methods

We used the Clinical Practice Research Datalink (CPRD), a database of routinely recorded primary care records from across the UK. CPRD is representative of the UK population and contains patient information from approximately 15% of the UK population. For each year from 1992-2017, the number of patients with a first Read coded record of GCA in that year, and aged 40 years or older at the time of diagnosis, was determined. The annual denominator population included the registered practice population without a prior record of GCA, aged 40 years or older. Annual incidence per 10,000 person-years (P-Y) at risk was derived overall and stratified by age, gender and region of the UK. Trends over time were modelled using Joinpoint regression. To be confident of the primary care diagnosis of GCA, a sensitivity analysis was undertaken which included a prescription of corticosteroids alongside the GCA Read code.

Results

There was a decrease in annual incidence of GCA in the UK between 1992 and 2017. Incidence was highest in 1994 (2.29/10,000 P-Y; 95% CI: 1.96, 2.67). This decreased to 1.51/10,000 P-Y in 2006, after which the incidence rates stabilised. Incidence rates for women were higher than men, irrespective of year. Incidence peaked between 70 and 89 years of age, with females aged 70-79 having the highest overall incidence rate of 5.20/10,000 P-Y (95% CI: 5.00, 5.40). The region of the UK with the highest incidence rate of GCA from 2015-2017 was Yorkshire & the Humber with 2.63/10,000 P-Y. The regions with the lowest incidence of 1.13/10,000 P-Y were the North East and West Midlands. Sensitivity analysis gave similar patterns.

Conclusion

The incidence of GCA in the UK has decreased slightly in recent years, which may reflect developments in more definitive early GCA diagnosis through fast-track clinics and improvements in imaging. However, further research into the presenting features of GCA in primary care is required. A set of early clinical features and comorbidities that are positively associated and predictive of a subsequent diagnosis of GCA would improve diagnosis and avert significant complications associated with delayed treatment.

Disclosures

L.A. Barnett None. T. Helliwell None. K. Jordan None. J. Prior None.
P03 Effectiveness and tolerability of Benepali in patients switched from Enbrel with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthropathy
Authors: Yeo Brandon , Dyball Sarah , Low Audrey
Published: April 2020

Background

Benepali (SB4) is an etanercept biosimilar licensed for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthropathy (AS) and is cheaper than Enbrel (ETN). We aimed to evaluate the effectiveness and tolerability of switching from ETN to SB4 and costs saved.

Methods

All patients on ETN were identified from pharmacy records and reviewed by consultants for clinical suitability to switch to SB4. Letters informing patients of the proposed switch were sent and replies collated. Patients were switched when prescriptions were due for renewal. Switching started in June 2018 and patients were prospectively followed at 3 and 6 months after switching. Anonymised demographic and clinical data were collected from patient records. DAS28 was calculated for RA and PsA due to availability of score components from patient records. The difference between disease activity scores prior to the switch, 3 months, and 6 months after switching was analysed using the Wilcoxon signed-rank test.

Results

113 patients were prescribed ETN and 17 patients were clinically unsuitable to switch. Of the remaining 96 patients, 6 declined switching and 7 stopped ETN before switching. The remaining 83 patients were switched from ETN to SB4 over a year and analysed (Table 1). Comparing measures of disease activity prior to switching versus 3 months or 6 months of follow-up on SB4, there were no statistically significant differences in disease activity for patients with RA (Table). Missing data for PsA and AS precluded statistical comparisons. 5 patients switched back to ETN due to subjective worsening of joint symptoms. 3 patients switched back to ETN due to adverse effects (infections, dizziness and nausea, unknown). 1 patient switched from SB4 to abatacept due to high disease activity. 1 patient stopped SB4 due to incident lung cancer.

Conclusion

SB4 was generally well tolerated with a retention rate of 88% (73/83) over 6 months of follow-up. In RA there was no significant difference in patients’ disease activity when switching from ETN to SB4, at 3 or 6 months of follow-up. Assuming all 73 switched patients remained on SB4 for a year, this would equate to £56,000 cost savings per year.

Disclosures

B. Yeo None. S. Dyball None. A. Low None.
P11 Review of pregnancy outcomes in patients with ankylosing spondylitis presenting to the Bart's Health High Risk Antenatal clinic: results of clinical audit and recommendations
Authors: Khudadah Mohammad , Jansz Sabrina , Saeed Aamir , Bickerstaff Maria
Published: April 2020

Background

Most patients with ankylosing spondylitis are diagnosed in their reproductive years and pregnancy can pose a challenge for the physician. Referral for preconception counselling, monitoring and management of these patients is best done in a multidisciplinary specialist clinic. To date, literature does not associate AS with adverse effects on pregnancy outcome. Patients can have unchanged, improved or active disease during pregnancy, however, postpartum flare is common.

Methods

We conducted a retrospective audit looking at pregnancy outcomes in patients referred to the High Risk Antenatal Clinic (HR-ANC) in our Trust between January 2014 and September 2019.

Results

A total of 18 patients with 22 pregnancies were found on our electronic system. Analysis showed an average number of visits to the clinic of 3.4 visits per patient with a median of 4. Only 45% had some form of preconception counselling prior to referral. 41% of the pregnancies were not exposed to any regular medications prior to conception. All other patients had their medications stopped after conception. 59% of pregnancies had medical induction of labour, 23% had a caesarian section. Median delivery was 39 weeks. The average birth weight was 3,022 grams, median 3,205 grams. 59% of the patients had antenatal disease flare and 45% had a postpartum flare. 32% of pregnancies did not have postpartum follow up.

Conclusion

Appropriate and thorough counselling should be offered to all patients with emphasis on disease course and management, safety of medications and neonatal vaccinations. Patients should be aware of a high chance of having active disease during pregnancy and the postpartum period. The rate of caesarian section in our patient cohort was not increased compared to the local rates in low risk pregnancies. These findings of disease activity in the antenatal and postpartum periods are consistent with published data. Good monitoring in a multidisciplinary clinic can lead to a successful outcome. Based on our findings, we are setting up a formal preconception counselling clinic for patients with AS with the following aims:

1. Family planning, including contraception advice.

2. Advice regarding medication use in the preconception, antenatal and postpartum periods.

3. Advice regarding disease course and expectations.

4. Advice regarding neonatal vaccinations, especially in patients on biological treatment.

5. Hot line for unplanned pregnancy and advice regarding medications and referral to the HR-ANC.

Disclosures

M. Khudadah None. S. Jansz None. A. Saeed None. M. Bickerstaff None.
P33 Spontaneous regression of confirmed diffuse large B-cell lymphoma after withdrawal of long-term methotrexate and infliximab therapy for rheumatoid arthritis, with concurrent discovery of rare high-grade urothelial carcinoma
Authors: Jones Bryony A , O'Callaghan Ann , Ross Emily V , Razack Aaron , Yusof Harliana , Wong Ernest
Published: April 2020

Background

A 73 year old man was diagnosed with diffuse large B-cell lymphoma germinal centre phenotype, after presenting with a 86x70x45mm right anterior chest wall lesion. CT CAP showed no further lymphadenopathy but identified an additional solid mass in the right ureter. The patient had been on methotrexate for 15 years and infliximab for 13 years for well controlled rheumatoid arthritis, and these were both discontinued on diagnosis of lymphoma. Within three weeks of discontinuation, the lymphomatous mass had clinically noticeably shrunk, confirmed radiologically, and on PET evaluation showed just low-grade avidity. However, the ureteric tumour was avid on PET, suggestive of second pathology. Biopsy proved high grade urothelial carcinoma with neuroendocrine differentiation. Chemotherapy to treat the urothelial carcinoma was identified as a priority, and carboplatin and etoposide chemotherapy was commenced which also has activity in lymphoma. Radiotherapy will be considered in the future, if indicated following further imaging.

Methods

A literature search was conducted on occurrence of lymphoma and urothelial carcinoma with anti-TNFα biologics.

Results

The link between methotrexate and increased risk of lymphoma is well covered in literature. Anti-TNFα biologic drugs have also been linked to lymphoma, but definitive causality is difficult to establish due to low numbers of cases and confounding factors. No cases were found in literature to associate anti-TNFα drugs with urothelial, transitional cell or neuroendocrine carcinomas. Eight case studies were found which show a temporal link between discontinuation of anti-TNFα and regression of lymphoma. Of these, six cases reported regression following withdrawal of infliximab. One case involved infliximab monotherapy, three had combination therapy with methotrexate, and two with azathioprine. One case reported discontinuation of adalimumab, with continuation of methotrexate. Histology showed two cases of low grade lymphoma, two case of Hodgkin’s lymphoma, and four cases of diffuse large B Cell non-Hodgkin’s lymphoma, similar to our patient case.

Conclusion

This patient presented with two synchronous tumours: diffuse large B cell NHL and high grade neuroendocrine carcinoma of urothelial tract. Whereas lymphoma regressed on withdrawal of methotrexate and infliximab, there was no change in the urothelial malignancy. Lymphoma regression allowed the urothelial malignancy to take priority for oncological therapy. It can be concluded that withdrawal of anti-TNF agents can allow spontaneous regression of lymphoma, and this can modify patient treatment plans.

Disclosures

B.A. Jones None. A. O'Callaghan None. E.V. Ross None. A. Razack None. E. Wong None.
P54 Development of ocular toxoplasmosis and panuveitis in a patient receiving infliximab for psoriatic arthritis
Authors: Malik Mariam , Anver Himashi , Wong Ernest
Published: April 2020

Background

Toxoplasma gondii is thought to infect up to a third of world’s population. Incidence rate of 0.4/100,000 has been calculated in Britain, culminating in a life-time risk of 18/100,000. Cats are primary hosts, but humans and warm-blooded animals can be infected by consumption of contaminated food/water. Although in most patients, it’s self-limiting, it can be devastating in immunosuppressed patients and may cause eye manifestations, cerebral abscesses or disseminated infection. Immunosuppressive therapies including treatment with biologics increases the risk and may also cause toxoplasmosis reactivation.

Methods

This is case of 57 year old lady with psoriatic arthritis. She has past history of congenital vision impairment in the left eye and is HLA B27 negative. She enjoyed horse-riding and had a pet dog. Initially she was started on methotrexate. Sulfasalazine was added later. Due to ongoing active disease, etanercept was used for 6 months, before being switched to cetrolizumab due to ineffectiveness. She had this for 5 months and then switched to infliximab, 3mg/kg, 8 weekly. In May 2019, she was seen by Ophthalmology for 2 weeks history of blurred vision and floaters in right eye. She was diagnosed to have panuveitis and had positive IgM for toxoplasma. Bloods revealed negative TB screen, HIV, Hep B&C, syphilis, lyme and anti-streptolysin antibody tests were negative. Infliximab levels were sub-therapeutic. She was commenced on 30mg prednisolone for possible inflammatory process secondary to seronegative arthropathy, but acute toxoplasmosis could not be excluded. Hence, she was started on azithromycin and had vitreous biopsy. Toxoplasma was detected in the sample, confirming acute infection. Methotrexate and infliximab were stopped. MRI head ruled out intracranial involvement. Following treatment of acute toxoplasmosis, adalimumab is now being considered for management of her inflammatory disease, with close monitoring by local infectious-disease team and specialist ophthalmology unit.

Results

This lady developed ocular toxoplasmosis and panuveitis, whilst on immunosuppression for psoriatic arthritis. She was a horse-rider and had exposure to dogs. Diagnosing toxoplasma in immunocompromised can be difficult. Isolation of T. gondii in tissue usually confirms diagnosis. Some forms of immunosuppressive treatment may be associated with increased risk of reactivation of toxoplasmosis but there is not much evidence to assess the relative risk of various therapies.

Conclusion

Ocular toxoplasmosis needs to be considered in patients receiving immunosupression and presenting with inflammatory eye symptoms. Management requires specialist input and close monitoring. Further research into diagnostic techniques, possibility of using prophylaxis in high-risk patients and management guidelines would be helpful.

Disclosures

M. Malik None. H. Anver None. E. Wong None.
P146 Undertaking an integrated nurse led review (INCLUDE) for patients with inflammatory conditions: does it change management of morbidities?
Authors: Hider Samantha , Machin Annabelle , Bucknall Milica , Cooke Kendra , Jinks Clare , Healey Emma , Finney Andrew , Cooke Kelly , Wathall Simon , Mallen Christian , Chew-Graham Carolyn
Published: April 2020

Background

People with inflammatory rheumatological conditions (IRCs), including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), are at an increased risk of common comorbidities, such as cardiovascular disease (CVD), osteoporosis and mood problems, which result in poorer patient outcomes. The INCLUDE study assessed the feasibility of conducting a randomised controlled trial (RCT) of a nurse-led, holistic, integrated review in primary care.

Methods

A pilot cluster RCT was delivered across four general practices. Patients with a Read code for an IRC were recruited by postal invitation. In intervention practices (n = 2), eligible patients were invited to attend a nurse-delivered INCLUDE review - an integrated consultation assessing CVD risk (QRisk2), bone health (FRAX) and mood (PHQ2 and GAD2), using a study-specific computerised template. Patients received an individualized patient management plan, including signposting to additional services as appropriate. Medical record review was undertaken (in consenting participants) at 12 months. We compared primary care contacts (which include consultations, letters and test results) and prescribing rates (of antihypertensives, lipid-lowering, osteoporosis and antidepressant/anxiety medication) at baseline and 12 months.

Results

333 patients participated in the study. The mean (SD) age was 68.2 (13.4) years and 200 (60%) were female. Of these 172 (52%) had RA and 88 (26%) had PMR. 154 (46%) reported high blood pressure, 70 (21%) existing anxiety/depression and 37 (11%) osteoporosis. Medical record data was available for 299/333 participants. Participants in intervention practices had more primary care contacts (mean 29 vs 22). Over the 12-month follow-up, there was higher prescribing of all medication classes in participants in intervention practices (see Table), particularly so for osteoporosis medication (baseline 29% vs 12 month 46%).

Conclusion

Nurse-delivered integrated reviews for patients with IRCs identified a significant comorbidity burden. Practices undertaking these reviews had higher prescribing rates at 12 months following treatment of previously un-identified conditions, suggesting that patients with IRCs would benefit from an integrated care review to identify and manage common morbidities.

Disclosures

S. Hider None. A. Machin None. M. Bucknall None. K. Cooke None. C. Jinks None. E. Healey None. A. Finney None. K. Cooke None. S. Wathall None. C. Mallen None. C. Chew-Graham None.
P190 Non-GCA diagnoses from a GCA fast track clinic: a single centre with four years' experience (2016-2019)
Authors: kayani Abdul , Sebastian Alwin , Ranasinghe Chavini , Whitlock Madeline , Hussain Hadi , Dasgupta Bhaskar
Published: April 2020

Background

Giant cell arteritis (GCA) has protean manifestations including temporal headache, visual disturbances, constitutional symptoms, jaw and tongue pain; symptoms which overlap with other conditions which mimic GCA. An important benefit of a fast-track clinic (FTC) is to rapidly exclude the diagnosis GCA to avoid inappropriate steroid exposure. We analysed data for patients referred with suspected GCA to our FTC where GCA diagnosis was subsequently excluded with fast-track ultrasound (US) and other investigations.

Methods

This retrospective data was extracted from the GCA fast-track electronic referral system at Southend University Hospital from January 2016 to July 2019.

Results

1,057 patients were seen at the fast-track clinic in this study period (Table 1). 690 (65.28%) were females. Only 15% (159) of the participants had a confirmed diagnosis of GCA (majority using US but also with other investigations such as biopsy or PET CT). Non-GCA patients accounted for 85% (898) and had a variety of differential diagnoses. In 222 (23.7%) no additional diagnosis was made after excluding GCA and patients were referred back for an expectant follow-up and assessment should any new features develop. In 204 (22.7%), polymyalgia rheumatica (PMR) was diagnosed with classical clinical symptoms and US of bilateral glenohumeral joints or response to a trial of low dose oral steroids. Another major group had different types of headaches 141 (15.71%) at presentation mimicking GCA. This included migraine 79 (56.0%), cervicogenic 58 (41.13%) and cluster headaches 4 (2.83%). Infectious causes were limited to head and neck infections 89 (9.91%) such as periorbital swelling, shingles and sinusitis. Neurological causes such as cervical spondylosis, cranial nerve palsy and TIA contributed to 7.9%. Chronic pain and other causes contributed 74 (8.24%) and 97 (10.8%) respectively. Other causes included medication-related (33), stress (21), cancer (4), RS3PE (4), glaucoma (2) and ANCA-associated vasculitis (33).

Conclusion

An FTP clinic not only diagnoses GCA rapidly but is also able to rapidly screen non GCA and prevent unnecessary steroid treatment. It also requires a screening tool like GCA probability score to triage referrals to enable a more efficient service.

Disclosures

A. kayani None. A. Sebastian None. C. Ranasinghe None. M. Whitlock None. H. Hussain None. B. Dasgupta Consultancies; Roche, Sanofi, GSK. Grants/research support; Roche.
P270 Comparing the visual analogue scale (VAS) and the numerical rating scale (NRS) in patient reported outcomes in PsA
Authors: Ye Weiyu , Hackett Simon , Vandevelde Claire , Twigg Sarah , Coates Laura C
Published: April 2020

Background

The visual analogue scale (VAS), a 100mm horizontal line, is commonly used for many outcomes including pain in psoriatic arthritis (PsA). However, it can be susceptible to measurement error. The numerical rating scale (NRS), a 21-point scale, overcomes these limitations, however, is not yet validated in PsA. We aimed to assess the agreement and reliability of the VAS and NRS scales in PsA.

Methods

Data was collected prospectively across three UK hospital trusts from 2018-2019. All patients completed VAS and NRS for pain, arthritis, psoriasis, and global disease activity. A subset was given an identical pack to complete one week later. Mean with standard deviation (S.D.) was calculated and variability assessed using the Bland-Altman method. Intraclass correlation coefficients (ICC, two-way mixed model absolute agreement) was used to assess test-retest reliability. All analyses were performed using R. This study was approved by London-Surrey Research Ethics Committee.

Results

210 patients completed the study; one withdrew consent thus 209 were analysed. 62 patients completed the scales one week later. 60.0% were male, mean age was 51.7 years, and median PsA duration was 7.0 years. The mean (S.D.) scores are detailed in the table. For all 4 variables, the difference between the VAS and NRS scales mostly lie within 1.96 S.D. of the mean, as assessed using the Bland-Altman method, suggesting reasonable agreement between the two scales. The NRS is preferred by patients. Comparing clinic and 1-week VAS scores, the ICCs for pain, psoriasis, arthritis and global disease activity were 0.91 (95% CI 0.84-0.94), 0.93 (0.87-0.96), 0.85 (0.74-0.91), 0.89 (0.81-0.93), respectively. For NRS, the ICCs for pain, psoriasis, arthritis, and global disease activity were 0.93 (0.88-0.96), 0.89 (0.82-0.94), 0.91 (0.84-0.94), 0.91 (0.85-0.95), respectively. This suggests both scales have excellent test-retest reliability.

Conclusion

The VAS and NRS scales show reasonable agreement in patient reported pain, psoriasis, arthritis and global disease activity, and thus the NRS could be used to measure these outcomes in patients with PsA. Considering its lower likelihood of measurement error, faster speed to score, and better acceptability to patients, the NRS offers a feasible alternative to the VAS in clinical practice.

Disclosures

W. Ye None. S. Hackett None. C. Vandevelde None. S. Twigg None. L.C. Coates: None.
The COVID-19 Global Pandemic: Implications for People With Schizophrenia and Related Disorders
Authors: Kozloff Nicole , Mulsant Benoit H , Stergiopoulos Vicky , Voineskos Aristotle N
Published: April 2020

The coronavirus disease-19 (COVID-19) global pandemic has already had an unprecedented impact on populations around the world, and is anticipated to have a disproportionate burden on people with schizophrenia and related disorders. We discuss the implications of the COVID-19 global pandemic with respect to: (1) increased risk of infection and poor outcomes among people with schizophrenia, (2) anticipated adverse mental health consequences for people with schizophrenia, (3) considerations for mental health service delivery in inpatient and outpatient settings, and (4) potential impact on clinical research in schizophrenia. Recommendations emphasize rapid implementation of measures to both decrease the risk of COVID-19 transmission and maintain continuity of clinical care and research to preserve safety of both people with schizophrenia and the public.
Mockticals: Student‐Directed Anatomy Mock Practical Exams in a Cadaver Laboratory
Authors: Kruse Amelia , Huetteman Helen , Harvey Rachel , Gemechu Jickssa , Barremkala Malli
Published: April 2020

The simulation testing process is helpful for students to test their knowledge of material (
Dobson, 2013), familiarize themselves with the exam format, and become acquainted with the high‐stress environment associated with test‐day. Although many schools conduct similar mock‐exams (
Nwachukwu et al, 2015;
McNulty et al, 2015), there is no literature to date standardizing how this should be performed or to provide evidence supporting the exam’s unique benefits to students who take it or organize it. This abstract demonstrates an effective model for implementation of the mocktical (mock‐practical) exam and its perceived benefits.

During the foundational anatomical course for first‐year medical students at Oakland University William Beaumont School of Medicine, students demonstrate their anatomy knowledge on four exams, each including written and laboratory components. Three first‐year students, designated as pod leaders (PLs), volunteer to organize and lead a mocktical the week prior to the actual exam. PLs are responsible for organizing a third of the mocktical and can take the remaining two‐thirds without advantage, so they start by splitting the 24 dissection tables into three pods. To generate well‐rounded test questions and tags, PLs delegate two categories to each table based on class material and dissection quality. Students may submit structures and the designated PL will prepare questions, or they may submit a structure and question together. The morning of the mocktical, anatomy course directors and PLs review all tags and questions.

Question categories include structures from cadavers, osteology, imaging, and histology. During the mocktical, students from each table take the exam in group format to simplify the movement of roughly 125 students through the lab. Nonetheless, each student takes the exam individually, maintaining silence, and each table will have no more than two questions. A timer is set for every 60 seconds to indicate that students should rotate, resulting in each group switching to the next table every two minutes. Total exam time is approximately 48 minutes. Upon completion, PLs display answer keys on in‐lab computers, and students are free to review and collaboratively discuss. Faculty are available for the next hour to answer questions and review topics of confusion. It should be noted that mockticals are in no way mandatory, yet we have observed nearly 99% participation, supporting the value of this process.
Cervical spinal V2a neurons pattern respiratory muscle activity and enhance ventilation
Authors: Jensen Victoria N. , Saeed Azl , Seedle Kari A. , Turner Sarah Marie , Crone Steven A.
Published: April 2020

Our prior studies suggested that one subset of V2a neurons activates accessory respiratory muscles whereas another subset of V2a neurons actively prevents their activation at rest. However, since these studies altered V2a neuron excitability throughout the spinal cord and brainstem, it was not clear whether the V2a neurons that activate accessory respiratory muscles are located in the same region of the neuraxis as V2a neurons that prevent activation of accessory respiratory muscles at rest. Therefore, we used a Cre‐dependent AAV virus injected into a Chx10Cre/+ mouse to selectively target either the excitatory (Gq)‐ or inhibitory (Gi)‐DREADD receptor to cervical spinal V2a neurons on one side or both sides of the cord in order to alter V2a neuron excitability. Whole breath plethysmography (WBP) and electromyography (EMG) were recorded in conscious mice at rest to measure ventilation and respiratory muscle activity before and after altering V2a neuron excitability. We found that bilaterally increasing the excitability of cervical spinal V2a neurons increases accessory respiratory muscle (scalene) activity, diaphragm EMG peak amplitude, and ventilation. Although V2a neurons project ipsilaterally, increasing their excitability on one side of the cord is able to synchronously activate scalene muscles on both sides of the body. Bilaterally silencing cervical spinal V2a neurons also activates scalene muscle activity, but does not impair diaphragm function. Our results are consistent with the hypothesis that one subset of V2a neurons in the cervical spinal cord activates accessory respiratory muscles whereas another subset of cervical V2a neurons inhibits accessory respiratory muscles at rest.

Support or Funding Information

1RO1NS112255T32NS5007453University of Cincinnati Dean’s Dissertation Completion Fellowship
Trafficking of a Resistance to Thyroid Hormone Syndrome Mutant: A Role of Calcium Signaling?
Authors: O’Dwyer Jerry
Published: April 2020

Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily that serve as transcription factors for thyroid hormone‐responsive genes. TRs undergo nucleocytoplasmic shuttling mediated by nuclear localization signals (NLS) and nuclear export signals (NES) that interact with importins and exportins, respectively. Mutations in TRs offset the balance between import and export, and TR mislocalization has been hypothesized to contribute to disease pathogenesis such as in cancer and Resistance to Thyroid Hormone (RTH) syndrome
(1). Severe bone malformations and delayed linear growth often characterize the phenotype of patients with RTH syndrome. A patient with a specific, atypical RTH point mutation in TRα1 (N359Y) also exhibit hypercalcemia
(2). The purpose of this study was to quantify the intracellular localization pattern of RTH(N359Y) and to test the hypothesis that calcium plays a role in regulating trafficking of this RTH mutant.

First, we performed in silico protein prediction modelling for both wild‐type TRα1 and RTH(N359Y). Both TRs have similar structure overall with perturbations in the DNA‐binding‐domain and Hinge domain. Transient transfection of HeLa (human) cells with GFP‐tagged wild‐type TRα1 and RTH(N359Y) were utilized to quantify the distribution patterns through the nuclear‐to‐cytoplasmic fluorescence ratio. RTH(N359Y) had similar localization patterns compared to wild‐type (p>0.05), with both receptors primarily localized to the nucleus. In contrast, when exposed to calcium‐enriched media, RTH(N359Y) showed a significantly increased nuclear localization compared to the wild‐type (p<0.05).

To further test our hypothesis, we examined the distribution patterns of a membrane‐associated, N‐terminal truncated TRα1, namely p30, which has been reported to associate with Caveolin‐1 in the lipid‐microdomain with other proteins involved with the cGMP‐NO signaling cascade
(3). Despite lacking the DNA‐binding‐domain, p30 reconstituted in MC3T3 lead to T3‐dependent proliferation. Therefore, if p30 localizes at the plasma membrane with Caveolin‐1, thyroid hormone stimulation could mediate import of calcium from the extracellular media and serve as an in vivo approach to test the impact of calcium on receptor trafficking for wild‐type TRα1 and RTH(N359Y). Confocal analysis, however, showed that GFP‐tagged p30 does not localize at the plasma membrane, up to 36 hours post‐transfection. Therefore, other approaches will need to be utilized to ascertain the role of calcium in the trafficking of this RTH mutant.

An understanding of how calcium regulates the trafficking of RTH(N359Y) could provide insight into the connection between RTH syndrome and hypercalcemia and more generally the synergistic role of calcium signaling and nuclear trafficking.

Support or Funding Information

NIH Grant #2R15DK058028 to L.A.A.
Knockout of Adam10 and Tfcp2l1 in mCCDcl1 Collecting Duct Cells Demonstrates Notch‐Dependent Cell Plasticity and Phenotype
Authors: Assmus Adrienne , Mullins Linda , Peter Audrey , Mullins John
Published: April 2020

The kidney cortical collecting duct (CCD) is responsible for the fine tuning of sodium, volume, and acid‐base homeostasis, and comprises of principal and intercalated cells (PCs and ICs) as well as a newly discovered ‘intermediate’ cell type
(1). Plasticity between PCs and ICs has been reported previously in mice in which genes for factors implicated in the Notch pathway, such as Adam10 and Tfcp2l1, have been knocked out (KO)
(2,
3). In vivo, disruption of the Notch pathway leads to a decreasing PC:IC ratio. The self‐immortalized mouse CCD cell line, mCCDcl1, shows functional characteristics of PCs and a response to physiological concentrations of hormones such as aldosterone; it also has been shown to express both PC and IC markers, a phenotype transmitted through single cell cloning
(4). These characteristics make mCCDcl1 cells a useful platform for the study of plasticity in the CCD. Tfcp2l1 and Adam10 were knocked out in mCCDcl1 cells using CRISPR‐Cas9 technology and independent clones were isolated and expanded for study. Despite mCCDcl1 cells being
polyploid, our strategy enabled all alleles for each gene to be successfully targeted and the knockout clones were verified using T7 endonuclease analysis, DNA sequencing and immunocytochemistry. Clones were cultured on Transwell filters over 10 days and their electrophysiological properties measured (trans‐epithelial resistance Rte, voltage Vte, calculated short‐circuit current Isc). Both Adam10 KO clones showed a slightly reduced baseline Rte compared to control (0.90±0.19 kΩ.cm2 vs 1.12±0.18 kΩ.cm2) but a complete reduction in baseline Isc (0.3±0.1 mA/cm2 vs −8.1±0.4 mA/cm2 for control) as well as aldosterone response, decreased by 95% (
fold change 0.19±0.03 down 3.70±0.11 for control). Both Tfcp2l1 KO clones failed to form a resistive cell monolayer, with a dramatic decrease in Rte compared to control (down to 0.10±0.02 kΩ.cm2) as well as a complete disappearance of baseline and epithelial sodium channel (ENaC) mediated amiloride‐sensitive
current. These data suggest that genomic modification of mCCDcl1 cells provides an effective means to investigate the mechanisms through which CCD cells mediate their plasticity and, in combination with single cell RNA‐Seq data, will identify new pathways involved in regulating cell phenotype.

Support or Funding Information

British Heart Foundation Centre for Research Excellence (BHF, RE/13/3/30183) Kidney Research UK (KRUK, RP/026/20180305)
Investigation into the Role of Histone H3 Lysine 4 in Developmental Gene Regulation
Authors: Anyetei-Anum Cyril S. , McKay Daniel J.
Published: April 2020

Histone H3 lysine 4 (H3K4) methylation is an evolutionarily‐conserved modification of chromatin closely linked to gene activation. H3K4 monomethylation (me1) is associated with active enhancers and flanks promoters. H3K4 dimethylation (me2) is enriched at tissue‐specific transcription factor binding sites, enhancers, and promoter edges. H3K4 trimethylation (me3) defines active transcriptional initiation at promoters. H3K4me1, me2, and me3 in Drosophila melanogaster is mediated by the methyltransferases Trr, dSet1, and Trx. The human homologs of these enzymes (MLL3/4, SET1A/B, and MLL1/2, respectively) perform conserved roles in human gene regulation and are commonly mutated in cancers. While these histone‐modifying enzymes have been found to be major regulators of development, differentiation, and disease, their enzymatic activity is not limited to histones and they also have non‐enzymatic functions. For these reasons, the specific role of H3K4 modification in transcriptional regulation is not understood. To directly test the function of H3K4 in animal development, we mutated H3K4 in Drosophila melanogaster. In this approach, the endogenous wild‐type histone genes are replaced with transgenic versions that have been mutated to encode a non‐modifiable residue (H3K4R). Notably, Drosophila is the only animal experimental system in which histone gene replacement can be performed because histone genes exist in high copy numbers and at multiple locations throughout the genome of most animals. By contrast, the canonical histone genes in Drosophila are clustered in a single chromosomal locus, allowing for its precise deletion
(1). Previously, we showed that wild‐type replacement transgene supports the propagation of a stable stock lacking all endogenous histone genes
(1). By contrast, here we find that H3K4R replacement transgenes result in embryonic lethality. Thus, H3K4 modification is essential for animal development. In future work, we will determine the effects of H3K4 mutation on gene expression through RNA‐seq analysis, as well as its impact on the histone post‐translational modification landscape through mass spectrometry. Together, this work will extend our understanding of the mechanistic role that histone modifications contribute to developmental gene regulation.

Support or Funding Information

NIH to DJM R35‐GM128851
Corticosteroid Biosynthesis Revisited: Substrate Specificity of Steroid 21‐Hydroxylase
Authors: Loke Steffen , Stoll Anna , Joseph Jan Felix , Machalz David , de la Torre Xavier , Botrè Francesco , Wolber Gerhard , Bureik Matthias , Parr Maria
Published: April 2020

Objective

Cytochrome P450 enzymes (CYPs) are capable of catalyzing regio‐ and stereo‐specific oxy functionalization reactions which otherwise are major challenges in organic chemistry. In order to make the best possible use of these biocatalysts it is imperative to understand their specificities.

Human CYP21A2 (steroid 21‐hydroxylase) is known as one important enzyme in the biotransformation of progestins into corticosteroids. Humans with a reduced activity of steroid 21‐hydroxylase suffer from congenital adrenal hyperplasia (CAH), that is characterized by reduced production of cortisol. Due to feedback mechanisms of the hypothalamic pituitary adrenal axis, increased concentrations of progestins, but also androgens resulting from alternative metabolic pathways are observed in these patients.

As enzymes in steroid biosynthesis are generally considered to show high substrate selectivity a closer investigation on structure requirements of steroid 21‐hydroxylase was conducted.

Methods

Biotransformation experiments were performed using a fission yeast expressing human CYP21A2 (CAD75) in a whole‐cell biotransformation assay
[1]. Progesterone, pregnenolone, and their corresponding 17‐hydroxy analogues were used as substrates. Product formation was monitored by GC‐MS. Molecular docking experiments were performed using GOLD software using the X‐ray structure of CYP21A2 co‐crystallized with progesterone (17, PDB entry 4Y8W
[2]) as protein conformation.

Results

An investigation on A‐ring requirements yielded that the presence of a 3‐oxo group is a strict prerequisite for a CYP21A2 substrate
[1]. In line with these findings the incubation of the endogenous progestins pregnenolone (3β‐hydroxy‐pregn‐5‐en‐20‐one) and 17α‐hydroxypregnenolone (3β,17α‐dihydroxy‐pregn‐5‐en‐20‐one) did not result in successful 21‐hydroxylation, while progesterone (pregn‐4‐ene‐3,20‐dione) and 17‐hydroxyprogesterone (17α‐hydroxy‐pregn‐4‐ene‐3,20‐dione) were hydroxylated at C‐21.

Molecular docking experiments supported the structure requirements. Apparently, the interaction of the carbonyl group at C‐3 of the substrate to the side‐chain Arg234 of the enzyme is indispensable.

Conclusions

The results are opposed to actual scientific view of steroid biosynthesis which for example supposes formation of 21‐hydroxypregnenolone is also catalyzed by CYP21A2
[3]. They also help to understand metabolic pathways of steroids in the human body and may be useful in further synthesis experiments due to the use of enzymes as biocatalysts.