bluuebunny/crossref_metadata_2025 huggingface dataset:
MUCE: Bayesian hierarchical modelling for the design and analysis of phase 1b multiple expansion cohort trials
Authors: Lyu Jiaying , Zhou Tianjian , Yuan Shijie , Guo Wentian , Ji Yuan
Published: April 2023

We propose a multiple cohort expansion (MUCE) approach as a design or analysis method for phase 1b multiple expansion cohort trials, which are novel first-in-human studies conducted following phase 1a dose escalation. In a phase 1b expansion cohort trial, one or more doses of a new investigational drug identified from phase 1a are tested for initial antitumour activities in patients with different indications (cancer types and/or biomarker status). Each dose–indication combination defines an arm, and patients are enrolled in parallel cohorts to all the arms. The MUCE design is based on a class of Bayesian hierarchical models that adaptively borrow information across arms. Specifically, we employ a latent probit model that allows for different degrees of borrowing across doses and indications. Statistical inference is directly based on the posterior probability of each arm being efficacious, facilitating the decision making that decides which arm to select for further testing. The MUCE design also incorporates interim looks, based on which the nonpromising arms will be stopped early due to futility. Through simulation studies, we show that MUCE exhibits superior operating characteristics. We also compare the performance of MUCE with that of Simon’s two-stage design and some existing Bayesian designs for multiarm trials. To our knowledge, MUCE is the first Bayesian method for phase 1b expansion cohort trials with multiple doses and indications.
The DNA replication initiation protein DnaD recognises a specific strand of the Bacillus subtilis chromosome origin
Authors: Winterhalter Charles , Pelliciari Simone , Stevens Daniel , Fenyk Stepan , Marchand Elie , Cronin Nora B , Soultanas Panos , Costa Tiago R D , Ilangovan Aravindan , Murray Heath
Published: April 2023

Genome replication is a fundamental biological activity shared by all organisms. Chromosomal replication proceeds bidirectionally from origins, requiring the loading of two helicases, one for each replisome. However, the molecular mechanisms underpinning helicase loading at bacterial chromosome origins (oriC) are unclear. Here we investigated the essential DNA replication initiation protein DnaD in the model organism Bacillus subtilis. A set of DnaD residues required for ssDNA binding was identified, and photo-crosslinking revealed that this ssDNA binding region interacts preferentially with one strand of oriC. Biochemical and genetic data support the model that DnaD recognizes a new single-stranded DNA (ssDNA) motif located in oriC, the DnaD Recognition Element (DRE). Considered with single particle cryo-electron microscopy (cryo-EM) imaging of DnaD, we propose that the location of the DRE within oriC orchestrates strand-specific recruitment of helicase during DNA replication initiation. These findings significantly advance our mechanistic understanding of bidirectional replication from a bacterial chromosome origin.
CSNK2B modulates IRF1 binding to functional DNA elements and promotes basal and agonist-induced antiviral signaling
Authors: Matsumoto Moe , Modliszewski Jennifer L , Shinozaki Kotomi , Maezawa Reona , Perez Vincent M , Ishikawa Yuki , Suzuki Ryosuke , McKnight Kevin L , Masaki Takahiro , Hirai-Yuki Asuka , Kohara Michinori , Lemon Stanley M , Selitsky Sara R , Yamane Daisuke
Published: April 2023

Interferon regulatory factor 1 (IRF1) is a critical component of cell-intrinsic innate immunity that regulates both constitutive and induced antiviral defenses. Due to its short half-life, IRF1 function is generally considered to be regulated by its synthesis. However, how IRF1 activity is controlled post-translationally has remained poorly characterized. Here, we employed a proteomics approach to identify proteins interacting with IRF1, and found that CSNK2B, a regulatory subunit of casein kinase 2, interacts directly with IRF1 and constitutively modulates its transcriptional activity. Genome-wide CUT&RUN analysis of IRF1 binding loci revealed that CSNK2B acts generally to enhance the binding of IRF1 to chromatin, thereby enhancing transcription of key antiviral genes, such as PLAAT4 (also known as RARRES3/RIG1/TIG3). On the other hand, depleting CSNK2B triggered abnormal accumulation of IRF1 at AFAP1 loci, thereby down-regulating transcription of AFAP1, revealing contrary effects of CSNK2B on IRF1 binding at different loci. AFAP1 encodes an actin crosslinking factor that mediates Src activation. Importantly, CSNK2B was also found to mediate phosphorylation-dependent activation of AFAP1-Src signaling and exert suppressive effects against flaviviruses, including dengue virus. These findings reveal a previously unappreciated mode of IRF1 regulation and identify important effector genes mediating multiple cellular functions governed by CSNK2B and IRF1.
Not4-dependent targeting of MMF1 mRNA to mitochondria limits its expression via ribosome pausing, Egd1 ubiquitination, Caf130, no-go-decay and autophagy
Authors: Chen Siyu , Allen George , Panasenko Olesya O , Collart Martine A
Published: April 2023

The Ccr4–Not complex is a conserved multi protein complex with diverse roles in the mRNA life cycle. Recently we determined that the Not1 and Not4 subunits of Ccr4–Not inversely regulate mRNA solubility and thereby impact dynamics of co-translation events. One mRNA whose solubility is limited by Not4 is MMF1 encoding a mitochondrial matrix protein. In this work we uncover a mechanism that limits MMF1 overexpression and depends upon its co-translational targeting to the mitochondria. We have named this mechanism Mito-ENCay. This mechanism relies on Not4 promoting ribosome pausing during MMF1 translation, and hence the co-translational docking of the MMF1 mRNA to mitochondria via the mitochondrial targeting sequence of the Mmf1 nascent chain, the Egd1 chaperone, the Om14 mitochondrial outer membrane protein and the co-translational import machinery. Besides co-translational Mitochondrial targeting, Mito-ENCay depends upon Egd1 ubiquitination by Not4, the Caf130 subunit of the Ccr4–Not complex, the mitochondrial outer membrane protein Cis1, autophagy and no-go-decay.
Depositing centromere repeats induces heritable intragenic heterochromatin establishment and spreading in Arabidopsis
Authors: Liu Zhang-Wei , Liu Jie , Liu Fengquan , Zhong Xuehua
Published: April 2023

Stable transmission of non-DNA-sequence-based epigenetic information contributes to heritable phenotypic variants and thus to biological diversity. While studies on spontaneous natural epigenome variants have revealed an association of epialleles with a wide range of biological traits in both plants and animals, the function, transmission mechanism, and stability of an epiallele over generations in a locus-specific manner remain poorly investigated. Here, we invented a DNA sequence deposition strategy to generate a locus-specific epiallele by depositing CEN180 satellite repeats into a euchromatic target locus in Arabidopsis. Using CRISPR/Cas9-mediated knock-in system, we demonstrated that depositing CEN180 repeats can induce heterochromatin nucleation accompanied by DNA methylation, H3K9me2, and changes in the nucleosome occupancy at the insertion sites. Interestingly, both DNA methylation and H3K9me2 are restricted within the depositing sites and depletion of an H3K9me2 demethylase IBM1 enables the outward heterochromatin propagation into the neighboring regions, leading to inheritable target gene silencing to persist for at least five generations. Together, these results demonstrate the promise of employing a cis-engineering system for the creation of stable and site-specific epialleles and provide important insights into functional epigenome studies and locus-specific transgenerational epigenetic inheritance.
Political Parties and Civility in Parliament: The Case of Australia from 1901 to 2020
Authors: Martínez Arranz Alfonso , Zech Steven T , Bonotti Matteo
Published: April 2023

Incivility in parliaments is always prominently displayed in media reports, often with the implicit or explicit commentary that the situation is getting worse. This paper processes and analyses the records of verbal interactions in the Australian Parliament for over 100 years to provide a first approximation on the evolution of civility. It provides a framework for understanding the multidimensional nature of civility that examines both ‘politeness’ and ‘argumentation’, with the latter grounded in notions of public-mindedness. The analysis focuses on the interactions between parties of the orators and the party in power, the chamber of utterance, and the year. The results indicate that instances of impoliteness have increased since the 1970s but only modestly and remain highly infrequent. Minor parties, particularly those representing right-wing and Green politics are more likely to use dismissive or offensive language than the dominant centre-left and centre-right parties, although direct insults and swearwords are the particular remits of right-wing ‘system-wrecker’ parties. All these minor parties, nonetheless, also display higher levels of argumentation in their interventions. This combination of aggressive language and increased argumentation highlights the pressures on minor parties to convey their points in a forceful way, a challenge that is particularly pressing in two-party systems like the Australian one.
OA03 Harnessing quantitative proteomics to identify biomarkers of treatment response to etanercept in patients with rheumatoid arthritis
Authors: Ling Stephanie F , Yap Chuan Fu , Nair Nisha , Bluett James , Morgan Ann W , Isaacs John D , Wilson Anthony G , Hyrich Kimme L , Barton Anne , Plant Darren
Published: April 2023

Background/Aims

Tumour necrosis factor inhibitors (TNFi) are commonly prescribed to treat rheumatoid arthritis (RA), but response to TNFi is not universal and there are no validated pre-treatment biomarkers of treatment response at present. Proteins have many features that make them ideal potential biomarkers, as they carry out diverse biological processes, interact with drugs and can reflect post-translational modifications. This study aimed to identify protein biomarkers associated with response to TNFi in patients with RA.

Methods

Participants were recruited from a UK-based prospective multi-centre study of patients fulfilling either the 1987 ACR or 2010 ACR/EULAR classification for RA starting biologic treatment for the first time. Quantitative proteomics was performed using Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) in sera from study participants before and after three months of treatment with the TNFi etanercept. Linear regression models were used to study the association between protein levels and the composite 28-joint count Disease Activity Score (DAS28) and its sub-components, adjusting for baseline covariates including age, biological sex disease duration and baseline DAS28. Sub-network analysis was carried out using the DIAMOnD algorithm, followed by functional enrichment analysis.

Results

Of the total 180 participants recruited, 134 (74.44%) were female, with a median age of 56.90 years and median pre-treatment DAS28 of 5.9. Eight individual proteins were found to be significantly associated with RA clinical outcome measures (see Table). Sub-network analysis identified the ontological theme with the strongest association as being positive regulation of response to endoplasmic reticulum (ER) stress (-log10(P) ∼ 7).

Conclusion

This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response and identified ER stress as an underlying pathway. The ER stress pathway has been previously reported to contribute to RA pathogenesis via synoviocyte proliferation and stimulation of pro-inflammatory cytokine production.

Disclosure

S.F. Ling: None. C. Yap: None. N. Nair: None. J. Bluett: None. A.W. Morgan: None. J.D. Isaacs: None. A.G. Wilson: None. K.L. Hyrich: None. A. Barton: None. D. Plant: None.
OA08 JAK inhibitors and the risk of malignancy: a meta-analysis across licenced disease indications
Authors: Stovin Christopher , Russell Mark D , Alveyn Edward , Adeyemi Olukemi , Patel Vishit , Adas Maryam A , Atzeni Fabiola , Ng Kenrick K H , Rutherford Andrew I , Norton Sam , Cope Andrew P , Galloway James B
Published: April 2023

Background/Aims

Concerns have been raised about the risk of malignancy with Janus kinase inhibitors (JAKi) following the ORAL Surveillance study, which reported an increased incidence of malignancy with tofacitinib compared with Tumor Necrosis Factor-α inhibitors (TNFi) in people with rheumatoid arthritis (RA) aged over 50 years who had additional cardiovascular risk factors. Our objective was to estimate the risk of malignancy for all licenced JAKi across disease indications, compared with TNFi, methotrexate (MTX), and placebo.

Methods

A systematic search of electronic databases (Medline, EMBASE, Cochrane) was performed to identify Phase 2/3/4 RCTs and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) in adults with RA, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease, or atopic dermatitis. Comparators were placebo, MTX, and TNFi. Random-effects meta-analysis was performed to compare malignancy incidence rates between JAKi and comparators. Our primary outcome measure was the incidence of all malignancies including non-melanomatous skin cancers (NMSC). Secondary outcomes were malignancies excluding NMSC, and NMSC only.

Results

In 62 eligible RCTs and 14 LTE studies, there were 71,767 person-years of exposure to JAKi; 2,680 to placebo; 7,827 to TNFi; and 1,074 to MTX. Comparing JAKi with placebo arms of RCTs, the incidence rate ratio (RR) for all malignancies including NMSC was not significantly different (RR 0.81; 95% CI 0.52 to 1.26; p = 0.36). Similarly, when comparing JAKi with MTX, no significant differences were observed in the incidence of malignancy (RR 0.73; 95% CI 0.33 to 1.61; p = 0.43). Compared with TNFi, however, administration of JAKi was associated with an increased incidence of malignancy (RR 1.54; 95% CI 1.19 to 2.01; p = 0.001). For all analyses, findings were consistent when excluding NMSC, when analysing NMSC only, and when including LTE data.

Conclusion

In trial settings, JAKi do not associate with an increased risk of malignancy compared with placebo or MTX, but are associated with an increased risk of malignancy relative to TNFi.

Disclosure

C. Stovin: None. M.D. Russell: Honoraria; Lilly, Galapagos, Biogen, Menarini. Other; Lilly, Pfizer, Janssen, UCB. E. Alveyn: None. O. Adeyemi: None. V. Patel: None. M.A. Adas: None. F. Atzeni: None. K.K.H. Ng: None. A.I. Rutherford: None. S. Norton: None. A.P. Cope: Consultancies; BMS, Abbvie, GSK/Galvini. Grants/research support; BMS. J.B. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB.
OA17 Patient values and what matters to patients with axial spondyloarthritis in clinic
Authors: Chan Antoni , Suarez Annabel , Rigler Kathryn , Hamilton Jill
Published: April 2023

Background/Aims

Physician-patient discrepancy in the goals of treatment remains an issue in axial spondyloarthritis (AxSpA). The National Axial Spondyloarthritis Society (NASS) has recently launched a national survey on patient values. Bridging the gap and improving alignment of physician-patient goals may lead to better outcomes. The objectives of this study were to investigate what patients wanted to discuss prior to their clinic attendance and to explore if these topics were discussed by the physician. The discrepancies between patient and physician goals were reviewed and steps put in place to bridge this gap.

Methods

Patients fulfilled the ASAS criteria for AxSpA. At baseline 130 consecutive patients attending the AxSpA clinic between April to December 2021 were sent a pre-clinic questionnaire. Patients were asked 2 questions and these were: 1) What do you wish to discuss at your appointment? 2) What goals do wish to achieve following treatment? Questionnaires were collected prior to the clinic. The medical notes and clinic letters were then reviewed post-clinic to check if questions 1 and 2 were discussed. The patient demographics and disease activity scores BASMI, BASFI and BASDAI were also collected.

Results

At baseline, 100/130 (77%) patients returned the questionnaire prior to clinic. The mean age was 41 years (range 23-67). 74 patients (74%) were male and 80 patients (80%) were in work. Patients were seen by a doctor (38%), specialist nurse (32%) and physiotherapist (30%). In terms of treatment, patients were currently on biologics (64%), NSAIDs (46%) and DMARDs (30%). The mean BASMI was 1.6 (range 0.2-5.4), BASFI 2.7 (0-9.2), BASDAI 3.5 (0.2-8.6) and CRP 3 (0-20). For pre-clinic question 1, the top three topics were medication, pain management and progression of disease. For question 2, the top three topics were to be pain-free, maintain flexibility and being mobile and active. There were also other topics that were raised including fatigue, sleep, infections and family planning. Post clinic, the topics in question 1 were discussed directly by the physician in 73% and question 2 in 59% of cases. The topics that were most discussed in clinic were medication, exercise and pain. Pooling the topics, the top five themes were pain, medication, flexibility, exercise and disease progression. A limitation is that the post clinic analysis was based on written clinic notes and letters.

Conclusion

This study confirms a degree of discordance in patient and physician goals. To bridge this gap, we are now focused on the top topics that patients wish to discuss in clinic and what they hope to achieve from their treatment. We have updated our AxSpA pathway to include these topics. Understanding patient goals will help us develop the content for the interventions and educational programmes to improve alignment and clinical outcomes.

Disclosure

A. Chan: None. A. Suarez: None. K. Rigler: None. J. Hamilton: None.
OA32 Jaw claudication - does the textbook description need updating?
Authors: Lim Joyce , Dures Emma , Bailey Lawrence , Almeida Celia , Ruediger Carlee , Hill Catherine , Robson Joanna , Mackie Sarah L
Published: April 2023

Background/Aims

Recognition of jaw claudication is crucial to expedite diagnosis and treatment of giant cell arteritis (GCA). The ACR 1990 criteria defined claudication of the jaw, tongue or deglutition as “development or worsening of fatigue or discomfort in muscles of mastication, tongue, or swallowing muscles while eating”. We sought to describe the diverse ways in which patients may describe this key GCA symptom and its impact on health-related quality of life.

Methods

Secondary analysis of a qualitative dataset originally created for the development of a patient-reported outcome measure for GCA. Participants (n = 36) with GCA confirmed by biopsy/imaging were recruited using purposive sampling from two rheumatology clinics and one ophthalmology clinic in the UK (n = 25) and Australia (n = 11). Interviews transcripts from the original study were organised within QSR NVivo 12 software and analysed using template analysis. Themes were refined through discussion among researchers including a patient partner.

Results

20 of 36 participants (56%) reported jaw symptoms. Of these 20, the median age was 76.5 years; 60% were female. Five main themes were identified in the data: physical sensations; impact on function; impact on diet; symptom response to steroids; attribution to other causes (see Table 1). Whilst a large proportion of patients described jaw pain, jaw cramp, jaw stiffness and lockjaw had also been described. Symptom resolution following commencement of steroids varied among participants. Jaw symptom was misjudged as due to dental cavity, ear infection and teeth grinding by healthcare professionals in some cases. Some patients did not seek immediate help from healthcare professionals regarding their jaw symptoms as they were thought to be related to arthritis, age or viral illnesses.

Conclusion

Patients with GCA described their jaw symptoms in various ways, not exclusive to chewing. When Horton originally described jaw claudication, he also observed that some patients reported ‘lockjaw’. For early recognition and prompt diagnosis of GCA, we suggest that textbooks and teaching should be updated to reflect this. Patient education on the potential significance of jaw symptoms is also crucial to avoid delay in seeking help.

Disclosure

J. Lim: None. E. Dures: None. L. Bailey: None. C. Almeida: None. C. Ruediger: None. C. Hill: None. J. Robson: None. S.L. Mackie: Consultancies; Roche/Chugai, Sanofi, AbbVie, AstraZeneca. Other; SLM has given talks on behalf of her institution for Pfizer, Vifor and UCB. In all cases fees were paid to her institution and no personal fees were received, SLM was supported by Roche to attend EULAR2019 and by Pfizer to attend ACR2021 virtually, SLM has been an investigator on clinical trials for Sanofi and GSK, As a research grant co-applicant, SLM has received research funding (partial salary support) from Vifor, paid to her institution.
P009 Navigating giant cell arteritis (GCA) service during and post COVID-19 pandemic: an audit of GCA care at North Bristol NHS Trust against the BSR quality standards
Authors: Lim Kian Wah , Shahriar Imran , Villar Sarah J , Sin Fang En
Published: April 2023

Background/Aims

GCA is a systemic vasculitis predominantly affecting the large vessels that requires prompt diagnosis and management. This clinical audit aims to study the impacts of COVID-19 pandemic on our GCA service and to identify areas for improvement to ensure good and safe practice amid healthcare crisis.

Methods

We audited referrals for suspected GCA from February 2021 until September 2022 and measured our patient care against the BSR quality standards. We performed retrospective data collection from digital care record systems and analysed our data using the IBM SPSS Statistics version 29.

Results

106 patients with suspected GCA were included, 73% were female and the mean age was 70 years. 75% of the referrals were from primary care. Main presenting symptoms were headaches (95.7%), scalp tenderness (69.6%), tongue/jaw claudication (52.2%), visual symptoms (47.8%), constitutional symptoms (43.5%) and polymyalgic symptoms (21.7%). 33% of patients were diagnosed and treated as GCA. Mean CRP was 23.9mg/L and mean plasma viscosity was 1.89mPA. The mean referral-to-specialist review time has reduced to 1.6 days, compared with 2.7 days pre-pandemic. All patients had vascular ultrasound but only 7.5% had a temporal artery biopsy (TAB), compared with 41% pre-pandemic. Table 1 compares expected and achieved BSR quality standards.

Conclusion

Changes in work pattern during the pandemic meant that the time from referral to specialist review was significantly reduced, by implementing twice weekly registrar-led ‘Hot’ clinics and reserving ad hoc slot(s) in on-call consultant’s clinics for GCA referrals. We have ramped up our vascular imaging capacity for vascular ultrasound during the pandemic in response to reduced surgical operating capacity for TAB. Strategies to address areas for improvement identified in this audit include: (1) clear and timely communication with referrer about steroid initiation and dosage, at the time of referral; (2) improving communication with primary care, emphasising need for urgent Ophthalmology input in patients with suspected GCA-related visual symptoms, through updating our regional GCA guideline for primary care; (3) standardising and implementing a GCA review proforma or checklist in our department to ensure that the BSR GCA care bundle is being implemented and addressed at the earliest opportunity.

Disclosure

K. Lim: None. I. Shahriar: None. S.J. Villar: None. F. Sin: None.
P010 Real world experience of switching to an adalimumab biosimilar; different outcomes for axial spondylitis, psoriatic and rheumatoid arthritis
Authors: Holden Francesca A A , Hill Diane , Kiely Patrick
Published: April 2023

Background/Aims

Adalimumab is licenced to treat a variety of autoimmune conditions including inflammatory arthropathies. Switching stable patients from the bio-originator Humira to biosimilars has been strongly promoted on economic grounds and presumed equitable interchangeability regarding efficacy and tolerance across all disease indications. Our aims were to assess adalimumab biosimilar retention rates up to 1 year in patients with axial spondylitis (AS), psoriatic (PsA) and rheumatoid arthritis (RA) in a routine care setting and to determine by disease subtype reasons for switching back to Humira.

Methods

Retrospective observational study, utilising data from the St. George’s Hospital Rheumatology Biologics Database. Demographic details, retention duration and reasons for discontinuation for all patients switched from Humira to an adalimumab biosimilar were recorded up to 1 year.

Results

238 patients (female 54.5%) were switched from Humira to an adalimumab biosimilar: AS n = 95, PsA n = 82, RA n = 61. Overall, 53% patients switched back to Humira over a 1-year period, female 57%. By disease subtype, the biosimilar retention rate at 1 year was AS 36%, PsA 61%, RA 46%. Overall, the reason for switching back to Humira was an adverse effect or device specific problem (AE) in 59% and loss of efficacy (IR) in 41%. AEs in 98% were pain and other injection site reactions. By disease subtype, the reason for switching back was: AS 59% IR, 41% AE, PsA 22% IR, 78% AE, RA 27% IR, 73% AE.

Conclusion

Projected cost savings from the adalimumab biosimilar switch programme were not achieved, with 53% returning to Humira up to 1 year later. By disease indication patients with AS had the lowest retention on the biosimilar, in whom loss of efficacy was more likely than an AE to trigger the switch, and over twice as prevalent than in patients with RA and PsA. AEs were the most prevalent reason for PsA and RA patients to switch back, and citrate in the biosimilar buffer solution was the likely reason for this. The loss of efficacy, particularly prevalent in AS patients, implies that equitable interchangeability between Humira and biosimilar products cannot be assumed, and projected cost saving advantages may be overestimated.

Disclosure

F.A.A. Holden: None. D. Hill: None. P. Kiely: None.
P012 Using the BSR Lupus audit as a springboard to improve management of SLE in the outpatient clinic
Authors: Benson Rosalind M , Cotton Caroline , Soares Ines , Mewar Devesh , Mclaren Zoe
Published: April 2023

Background/Aims

In 2018, following BSR Lupus guidelines publication, we took part in the national multicentre Lupus audit. Audit standards developed by expert consensus to assess baseline care in the outpatient management of SLE were used. We present a series of audit cycles spanning the development of a connective tissue disease (CTD) service and a trust merger capturing quality improvement work that has been informed by audit results.

Methods

In 2018, participating in the BSR audit, 15 patients attending a non-specialist rheumatology clinic over a 4-week period were enrolled. In 2019, Liverpool University Hospitals NHS Foundation trust was formed following the merger of two large teaching hospitals. A trust-wide CTD service was established in 2020. The audit was repeated in 2020 including all 119 patients seen over a 12-month period with SLE. Conclusions informed two QI workstreams: urine sample collection and the development of an SLE review form for the electronic notes and electronic SLEDAI score. A further audit cycle was performed including 40 patients following the implementation of these changes selecting patients across both hospital sites seen both in general and specialist clinic settings.

Results

In 2018, 5/11 audit standards were met, 3/11 in 2020. In 2022 across all clinics 4/11 standards were attained, however this improved to 9/11 in the specialist clinic (see table).

In 2020, only 22% of patients had their urine tested; following a QI project (including nurse education and inclusion on clinic observation form) this improved to 90%.

Following introduction of the electronic SLE review form, when used, audit standards were met in all areas (9/11) apart from lipid testing and discussion of pregnancy (79% of patients vs standard of 80%).

Conclusion

Using the BSR audit as a tool to spearhead QI projects in our newly merged trust and CTD service, clear improvements have been made. The development of an SLE review form which can be used in all non-specialist rheumatology clinics prompts clinicians to target key audit standards, in turn improving patient care. Further departmental implementation will help drive further improvement with particular focus on SLEDAI assessment and lipid monitoring.

Disclosure

R.M. Benson: None. C. Cotton: None. I. Soares: None. D. Mewar: None. Z. Mclaren: None.
P018 Non-alcoholic fatty liver disease in spondyloarthritis: identifying patients on therapy at high risk of serious liver disease
Authors: Harrison Stephanie R , Nandasoma Udvitha , Parker Richard , Chimakurthi Chenchu , Laws Philip , Barr Andrew , Vandevelde Claire , Marzo-Ortega Helena , Freeston Jane
Published: April 2023

Background/Aims

People with Spondyloarthritis (SpA), especially those with psoriatic disease (PsD) [psoriasis (PsO) and psoriatic arthritis (PsA)], are at higher risk of non-alcoholic fatty liver disease (NAFLD) due to increased prevalence of metabolic syndrome, obesity, hypertension, dyslipidaemia and disease-specific factors such as duration/ severity of psoriasis. There is significant concern that both synthetic and biological DMARDs (including methotrexate) may worsen liver function in PsD patients with NAFLD. The Leeds Teaching Hospitals Trust (LTHT) NAFLD pathway uses three screening tools (ELF, FIB-4 and fibroscanning) to identify those needing further investigation/ treatment by hepatology. However, the pathway is not validated in PsD. Our aim was to survey the prevalence of liver disease in our PsD population and explore the performance of our hepatology referral pathway.

Methods

We audited consecutive patients referred from the Leeds Specialist SpA service at LTHT with persistently abnormal ALT, whom the consultant Rheumatologist felt required Hepatology referral for suspected NAFLD. Data collected were: age, sex, BMI, history of diabetes, ALT, AST, platelets, albumin, hepatitis B and C, ELF score, FIB-4 score, fibroscan score, abdominal ultrasound, liver biopsy result and final hepatology diagnosis (NAFLD, fibrosis/cirrhosis or other).

Results

72 patients were included; 84.2% had PsD (61/72), and 15.8% (11/62) had ‘Other’ forms of SpA (including axial spondyloarthritis, enteropathic arthritis, etc). Baseline characteristics, drug treatment and liver biochemistry/virology were similar between PsD and Other arthritis groups (Table 1) except for age which was lower in the Other. The average ELF scores were similar between PsD and Other, however FIB-4 scores were higher in PsD, and was associated with higher rates of fibrosis/cirrhosis (Table 1). FIB-4 >1.3, but not ELF>9.5, was statistically significantly associated with a high fibroscan score (p = 0.038 and p = 0.443 respectively).

Conclusion

PsD patients had higher rates of significant fibrosis/cirrhosis compared with patients with Other SpAs. FIB-4 was better than ELF for identifying which PsD patients required fibroscan and further investigation to exclude significant fibrosis/ cirrhosis. These findings will now be validated in a larger prospective study.

Disclosure

S.R. Harrison: None. U. Nandasoma: None. R. Parker: None. C. Chimakurthi: None. P. Laws: None. A. Barr: None. C. Vandevelde: None. H. Marzo-Ortega: None. J. Freeston: None.
P043 Income-Related Health Inequality and Osteoarthritis Intervention Outcomes: a Cohort Study
Authors: Battista Simone , Kiadaliri Ali , Englund Martin , Jönsson Thérése , Gustafsson Kristin , Testa Marco , Dell'Isola Andrea
Published: April 2023

Background/Aims

Osteoarthritis (OA) management programmes have been lately developed to tackle the osteoarthritis burden. Though beneficial, OA management programmes can be less effective on people in lower socioeconomic positions and widen the possible pre-existing inequalities gap (‘intervention-generated inequalities’). In Sweden, an OA management programme was implemented in the national healthcare system, including exercise and education. Its results are recorded in the ‘Better Management of People with Osteoarthritis’ (BOA) register, one of the most extensive OA datasets worldwide. Hence, this study investigated the influence of this Swedish osteoarthritis management programme on income-related inequality.

Methods

A register-based study with data from the BOA register. We calculated Erreygers’ and Wagstaff’s concentration indices and how they changed throughout time. We considered the variables ‘Pain intensity’, ‘Self-efficacy‘, ‘Use of NSAIDs’ and ‘Desire for surgery’ at three-time points (baseline, after three and twelve months from the beginning of the programme). Concentration indices’ values range from -1 to + 1. Zero indicates no income inequality. A positive (or negative) sign indicates an unequal concentration of the variables of interest among those with higher (or lower) income. We used bootstrapping (1000 replications) to compute 95% confidence intervals for changes in the concentration indices from baseline.

Results

A total of 115,403 people with knee and hip OA were identified. ‘Pain intensity’ and ‘Desire for surgery’ were disproportionately concentrated among those with lower income at the baseline, while the opposite happened for ‘Use of NSAIDs’ and ‘Self-efficacy’ (Table 1). Income inequalities for ‘Pain intensity’, ‘Self-efficacy’ and ‘Desire for surgery’ widened following the programme, though their magnitude was small. Conversely, income-related inequality in the ‘Use of NSAIDs’ narrowed after attending the programme.

Conclusion

Considering the concentration indices’ values, people with lower income were already experiencing higher levels of pain and desire for surgery and lower levels of self-efficacy than their higher counterparts. This trend got even worse after attending the abovementioned programme. Instead, people with higher income were keener on using NSAIDs but attending this programme narrowed this gap. These results highlighted ‘intervention-generated inequalities’ in the BOA data. OA management programmes should be structured to reduce inequalities among people with different incomes.

Disclosure

S. Battista: None. A. Kiadaliri: None. M. Englund: None. T. Jönsson: None. K. Gustafsson: None. M. Testa: None. A. Dell'Isola: None.
P053 Patient engagement in long-term PROMs collection: 48-month observation in real-world clinical practice
Authors: Biliavska Iuliia , Lenguerrand Erik , Sparey Esme , Tobias Jon H , Hamann Philip D H
Published: April 2023

Background/Aims

Patient-reported outcome measures (PROMs) allow effective communication of disease experiences and encourage shared decision-making for people with inflammatory arthritis (IA). This analysis examines the long-term utilization of PROMs collection in a real-world clinical environment.

Methods

Clinical practice review at North Bristol NHS Trust rheumatology clinic (July 2018 - July 2022), focussing on PROMs collection (joint assessment (self-JA), HAQ, RAPID3) from patients with IA, using a smartphone-based diary (Living With) to assess and record disease activity. The app is GDPR and NHS Data Security and Protection Toolkit (ODS Code 8JP33) compliant. Ethical approval wasn’t required for this service review. Data were fully anonymized prior to analysis. Statistical analysis was completed in RStudio (V.1.4.1717). Kaplan-Maier analysis estimated app engagement. “Long-term” users were defined as those completing ≥1 PROM over 12 weeks before data cutoff. Participants recruited ≤16 weeks before data cutoff were excluded.

Results

Over 48 months, 1257 patients were invited and 967 (76.9%) downloaded the app.711 (56.6%) completed a PROM at least once. 79 (11.1%) were excluded due to diagnosis change out of IA group. Among 632 IA patients: 69.1% were female, mean age was 53.7±13.9 years. 63.7% had rheumatoid arthritis, 25.2% psoriatic arthritis; 7.4% undifferentiated IA, 2.1% enteropathic, 1.6% reactive arthritis, respectively. Recruitment increased over time with a noticeable rise in April 2020. The median number of completed RAPID3 was 9 [4; 30], self-JA - 9 [3; 26] and HAQ - 4 [1; 10]. 71.8% of recruited patients completed all PROMs; 15.8% - two PROMs and 12.3% - at least once. Median time in days from registration to first completed RAPID3 was 1 [0; 15], self-JA - 2 [0; 23] and for HAQ - 3 [0; 30]. Table 1 shows the proportion of “long-term” app users. The median duration of engagement was: RAPID3- 64.1 95%CI [36.9; 55.0], self-JA -57.9[52.7; 65.1], HAQ - 44.3 [36.9; 55.0] weeks.

Conclusion

Engagement in PROMs collection has markedly increased since 2020 but does decrease over time. Ongoing encouragement from health professionals to use and integrate PROMs into care pathways is essential and provides valuable information on the effectiveness and tolerability of health interventions.

Disclosure

I. Biliavska: None. E. Lenguerrand: None. E. Sparey: None. J.H. Tobias: None. P.D.H. Hamann: Consultancies; provided consultancy for Living With Ltd Software Company for the development of the smartphone application -Living With Rheumatoid Arthritis. Royalties; limited royalty agreement with Living With Ltd Software Company. Honoraria; from Gilead Pharmaceuticals for the production of training materials on remote monitoring for patients with arthritis.
P058 Pneumocystis Jirovecii Infection in autoimmune inflammatory rheumatic diseases in Oxford
Authors: Verdiyeva Ayna , Siosi Alexa Escudero , Andersson Monique , Woodrow Charles , Dubey Shirish
Published: April 2023

Background/Aims

Pneumocystis jirovecii pneumonia (PJP) is a rare but frequently fatal fungal infection, which can affect patients with rheumatic diseases treated with immunosuppressants or high doses of corticosteroids. The only guidelines for primary prophylaxis of this infection are for vasculitides treated with cyclophosphamide or rituximab. The aim of this abstract is to raise awareness of this preventable infection and to highlight the urgent need to create a tailored risk assessment algorithm to identify patients at increased risk of this infection.

Methods

We collected information on patients with autoimmune inflammatory rheumatic diseases (AIIRD) who had final working diagnosis of PJP from January 2021 to July 2022 in Oxford University Hospitals NHS Foundation Trust. Patients were identified through infection, respiratory and rheumatology teams. Electronic notes were reviewed to collate clinical data.

Results

We identified 11 patients who had definite or probable PJP infection of which 7 were female. Of these, 6 were being treated for large vessel vasculitis (LVV), 3 had rheumatoid arthritis (RA) and 2 patients had connective tissue disease (CTD). Median age was 78 years (range 46-93 years). 10 patients had lymphopenia with lymphocyte count <1x10^9/L (the only patient without lymphopenia had chronic lymphocytic leukaemia (CLL)). Prednisolone was prescribed in combination with disease modifying anti-rheumatic drugs (DMARDs) in 6 patients and monotherapy (high dose) in 3 patients, whilst 2 patients were on DMARDs/biologic only. None of the patients who developed PJP had been given prophylaxis prior to the infection. All patients were treated with cotrimoxazole or atovaquone (in one case) for PJP. Unfortunately, 4 died from PJP infection. All these patients were taking 20-60mg prednisolone. Summary patient characteristics are shown in the table below.

Conclusion

PJP appears to be more common than is currently recognised. Prescribing PJP prophylaxis is not standard practice for patients with CTD and LVV. Consideration needs to be given to PJP prophylaxis for patients on high dose corticosteroids for a prolonged period, particularly in the presence of other risk factors. Better screening mechanisms are needed to identify those patients who will benefit most from PJP prophylaxis.

Disclosure

A. Verdiyeva: None. A. Escudero Siosi: None. M. Andersson: None. C. Woodrow: None. S. Dubey: None.
P070 Results of a consensus process to determine the elements of a complex digital intervention for distal upper limb musculoskeletal disorders
Authors: Brading Lucy , Kane Kathleen , McHugh Gretl , Dziedzic Krysia , Adams Jo , Chopra Swati , Swaithes Laura , Walker-Bone Karen , Macfarlane Gary , Conaghan Philip , Kingsbury Sarah
Published: April 2023

Background/Aims

Painful distal upper limb (DUL) musculoskeletal disorders (MSDs), including hand, wrist and elbow problems, are common but lack effective self-management tools. The Digital-My Arm Pain Programme (D-MAPP) aims to develop and test a digital self-management intervention for DUL-MSDs. This project aimed to determine the elements required for the D-MAPP intervention package.

Methods

A review of self-management interventions for DUL-MSDs identified 31 potential intervention elements. Subsequently, the elements were grouped into three overarching categories; Information and self-management advice, Information on treatment options, and Features of an exercise programme. Next, we employed Delphi methodology to develop consensus on the intervention elements from key stakeholders: Healthcare professionals who manage DUL-MSDs and people with a DUL-MSD (pwDUL-MSDs). A three-round modified online/postal Delphi questionnaire was used, with collation and presentation of results in subsequent rounds. Participants scored the importance of including each element in the D-MAPP intervention using a 9-point Likert scale; 1-3 limited importance, 4-6 important but not critical, 7-9 critical. Consensus was pre-defined as > 70% of both healthcare professionals and pwDUL MSDs scoring an element in the same category. During each round, participants could suggest additional intervention elements for inclusion in the subsequent round.

Results

23 healthcare professionals from a range of disciplines (including occupational therapists, physiotherapists, rheumatologists and orthopaedic surgeons) and 19 pwDUL-MSD completed round one; 83% and 89%, respectively, completed all three rounds.

Round 1, consensus was achieved for 24 of the 31 elements, which were all deemed as critical to include in the D-MAPP intervention (Table 1). Two elements were suggested by participants and added to round 2. Two additional elements reached consensus as being critical in Round 2, and one further element reached consensus for inclusion in the third round. Six potential intervention elements did not reach a consensus.

Conclusion

Healthcare professionals and patients reached consensus on 27 elements, all of which were deemed as critical to include in the D-MAPP intervention. However, agreement among stakeholders on the importance level was not achieved for six potential elements. Following this work, the critically important elements will be developed through a co-design process to build the D-MAPP digital intervention.

L. Brading: None. K. Kane: None. G. McHugh: None. K. Dziedzic: None. J. Adams: None. S. Chopra: None. L. Swaithes: None. K. Walker-Bone: None. G. Macfarlane: None. P. Conaghan: None. S. Kingsbury: None.
P082 Research priorities regarding the use of bisphosphonates for osteoporosis: a UK priority setting exercise
Authors: Paskins Zoe , Moult Alice , Corp Nadia , Bastounis Anastasios , Davis Sarah , Narayanasamy Melanie Jay , Griffin Jill , Gittoes Neil , Leonardi-Bee Jo , Langley Tessa , Bishop Simon , Sahota Opinder
Published: April 2023

Background/Aims

Worldwide, many people who would benefit from osteoporosis treatment are not offered or receiving them, resulting in an osteoporosis care gap. Adherence with bisphosphonates is particularly low. This study aimed to identify stakeholder research priorities relating to bisphosphonate regimens for the treatment of osteoporosis.

Methods

A three-step approach based on the James Lind Alliance methodology for identification and prioritisation of research questions was used. Research uncertainties were gathered (Step 1) from recent published international clinical guidelines and a large programme of related research studies about bisphosphonate regimens: the ‘Bisphosphonate aLternAtive regimenS for the prevenTion of Osteoporotic Fragility Fractures’ (Blast Off) study, which consisted of six discrete individual research studies conducted between May 2019 and February 2022, relating to the experience, effectiveness and cost-effectiveness of different bisphosphonate regimens. Clinical and public stakeholders refined the list of uncertainties into research questions (step 2) and then prioritised the questions using a modified nominal group technique (step 3) in two, day-long online workshops.

Results

In total, 34 draft uncertainties were finalised into 33 research questions by stakeholders. Twenty nine stakeholders were involved in refining uncertainties and prioritisation, including 16 public contributors, 2 Allied Health Professionals, 3 GPs and 8 Consultants. The top 10 questions are shown in Table 1.

Conclusion

This study reports, for the first time, topics of importance to stakeholders in the research of bisphosphonate osteoporosis treatment regimens. The priorities address how to better implement guidelines to address the care gap, understanding patient factors influencing treatment selection and effectiveness, and how to optimise long-term care. These findings have implications for research into implementation to address the care gap and education of healthcare professionals in the treatment of osteoporosis.

Disclosure

Z. Paskins: None. A. Moult: None. N. Corp: None. A. Bastounis: None. S. Davis: Grants/research support; Grant from Roche Diagnostics to her employing insitution to fund research into the cost-effectiveness of using a biomarker to monitor response to treatment with antifracture medication. M. Narayanasamy: None. J. Griffin: None. N. Gittoes: None. J. Leonardi-Bee: None. T. Langley: None. S. Bishop: None. O. Sahota: None.