bluuebunny/crossref_metadata_2025_split huggingface dataset:
P106 Feasibility Study of Methotrexate use Improvement in Rheumatoid Arthritis using Biomarker Feedback: The MIRA Trial
Authors: Bluett James , Hyrich Kimme L , Keevil Brian , Doran Patty , Barton Anne 
Published: April 2023

Abstract

Background/Aims
MTX non-adherence is associated with reduced response, increased healthcare costs to the NHS and reduced quality of life for the patient. Often the prescriber is unable to determine if a patient is taking their medication as prescribed. There is a need to measure adherence directly to facilitate more precise and objective measurements of adherence to add to the clinicians tools and help to open up honest discussions and supportive interventions with patients. Our group has previously developed a sensitive biochemical assay for the detection of MTX adherence, MIRA is a feasibility trial designed to assess the feasibility of a randomised controlled trial of MTX biochemical adherence biofeedback.

Methods
MIRA is a prospective multi-centre randomised controlled trial to examine the feasibility of a fully powered randomised controlled trial to examine if a biochemical adherence guided intervention is superior to standard clinical care in RA patients prescribed MTX. RA patients prescribed oral MTX for ≥ two years were randomised 1:1 to receive biochemical adherence biofeedback or control. Clinico-demographics, biochemical MTX adherence and DAS-28 and were measured at baseline and three months. Participants in the intervention cohort were telephoned with their biochemical adherence results and adherence was explored. Ethical approval for MIRA was given by the North West - Haydock Research Ethics Committee (19/NW/0047) and all participants provided written informed consent.

Results
57 participants were recruited, withdrawal rate was 14% and reasons given were intercurrent illness, lost contact, withdrawn consent and one patient died during follow-up leaving full outcome data available for 49 participants. Baseline clinico-demographics were similar in control and intervention cohorts (Table 1). Biochemical adherence worsened in the control cohort and improved in the intervention cohort (17 to 30%, 15 to 8% respectively). Change in DAS(CDP)-28 during the trial worsened in the control cohort but improved in the intervention cohort (-0.04 STD 1.26 and 0.38 STD 0.78 respectively).

Conclusion
The results of the MIRA trial have demonstrated that the use of a biochemical adherence blood test with biofeedback is feasible as part of a clinical trial. The intervention demonstrated early evidence for efficacy justifying the need for a full definitive trial.
Disclosure
J. Bluett: None. K.L. Hyrich: None. B. Keevil: None. P. Doran: None. A. Barton: None.
P123 Biologic dose tapering: a patient perspective
Authors: Rahman Rayan , Beynon Celia 
Published: April 2023

Abstract

Background/Aims
Biological therapies target specific pathways within the inflammatory process involved in the pathogenesis of rheumatoid arthritis. They are costly and can be associated with side-effect burden for patients. Evidence on whether medications can be stopped or tapered in stable patients in remission or very low disease activity is limited. This approach may benefit by limiting side-effects and costs. Alongside understanding the efficacy of dose tapering it is also necessary to gain insight into how patients perceive this approach. Our aim was to identify key themes that arise when patients discuss their perspective on biologic dose tapering.

Methods
213 rheumatoid arthritis patients in the Cardiff & Vale Health Board on sub-cutaneous anti-TNF agents (certolizumab, etanercept, adalimumab, golimumab) were identified. An inclusion/exclusion criterion was then formulated after consultant review to determine which patients were in remission/low disease activity and may be suitable for dose tapering. 80/213 patients qualified, and a digital questionnaire was sent to 52/80 patients where 23/52 (44% response rate) of the patients responded. The questionnaire included single and multiple response questions. Open text answers were also available if patients wanted to include any other comments. The questionnaire focused on 4 main insights: Knowledge, Experience, Perspective and Practicalities. Questionnaire data was then thematically analysed.

Results
3 themes became prominent: [1] Hesitancy, [2] Fear, and [3] Information. [1] 83% of patients had never heard of dose tapering before the questionnaire, 61% were ‘unsure’ in their initial thoughts of dose tapering and 30% were ‘unsure’ in being considered for dose tapering. This indicates how limited understanding may contribute to patient hesitancy. [2] 18% of patients were initially ‘fearful’ and 61% of patients were afraid of ‘flaring’ again. Patients were fearful of the ‘length of time they need to wait for an appointment’ if they flared, with 57% of patients wanting ‘access to help if there was flare’. The concept of fear was multi-faceted occurring in both patients’ concerns surrounding their disease activity and practicalities related to care. [3] 35% of patients believed they did not have enough ‘information’ and 45% believed receiving more ‘information’ about tapering would make them more comfortable with the idea.

Conclusion
The hesitancy and fear patients had may be associated with the limited exposure and information they had of dose tapering - demonstrating this initial information barrier. Patients preferred mode of contact would be virtual and face-to-face support, or just solely face-to-face. 83% of patients preferred Rheumatologists as their main source of information for dose tapering, and discussed how leaflets, case histories and websites may help in future discussions surrounding dose tapering. These patient perspectives will help us to develop and implement a dose tapering strategy for our department.
Disclosure
R. Rahman: None. C. Beynon: None.
P129 DNA methylation of the tumour necrosis factor gene as a biomarker of diagnosis in early rheumatoid arthritis patients
Authors: Liu Melanie C , Ng Helen , Anioke Innocent , Ponchel Frederique 
Published: April 2023

Abstract

Background/Aims
Rheumatoid arthritis (RA) is an autoimmune inflammatory condition that affects the synovial joints. RA exists on a disease continuum where immunological changes occur before the onset of clinical symptoms. Changes in DNA methylation status of genes are thought to be early triggers of the progression from health to disease. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that contributes to RA. Recently it has been shown that the loss of DNA methylation in the promoter region of the TNF gene is related to early RA. This study aims to establish the predictive value of the levels of DNA methylation of the TNF gene as a biomarker for diagnosis of RA.

Methods
Blood samples from a retrospective cohort of patients with symptoms of inflammatory arthritis between 2010 and 2019 at the Leeds Early Arthritis Clinic were selected. Data obtained include clinical symptoms of disease progression over 2 years to establish a diagnosis. DNA methylation levels of the TNF gene were measured by quantitative polymerase chain reaction (qPCR) and analysed using binary logistic regression with forward (LR) variable selection for added value as a diagnostic biomarker.

Results
For the 284 patients with a mean age of 53.8, 202 (71.7%) were female and 82 (28.9%) were male. From N = 284, 190 (66.9%) were diagnosed with RA and 94 (33.1%) with another conditions. The predictive accuracy of the regression model was increased by 3.5% from 85.8% to 89.3% when TNF DNA-methylation levels was added to demographic and clinical variables. The AUC of the model with TNF was 0.940 compared to 0.911 without TNF DNA-methylation levels. The sensitivity and specificity of the prediction with DNA methylation data were 94.6% and 77.9% respectively. This TNF model has a positive predictive value of 90.2% and a negative predictive value of 87.0%.

Conclusion
DNA methylation of the TNF gene is an important biomarker for RA diagnosis. This study showed that including levels of TNF DNA-methylation improves the accuracy of diagnosing RA.
Disclosure
M.C. Liu: None. H. Ng: None. F. Ponchel: None.
P133 Attitudes to Technology supported Rheumatoid Arthritis care: Opportunities & Barriers for technology in RA - Key themes from Qualitative arm of Mixed-Methods Study
Authors: MacBrayne Amy , Curzon Paul , Soyel Hamit , Marsh William , Fenton Norman , Pitzalis Costantino , Humby Frances 
Published: April 2023

Abstract

Background/Aims
Rheumatoid arthritis (RA) outcomes have significantly improved with the treat-to-target paradigm, however this necessitates intensive monitoring. Demand outstrips capacity in rheumatology services, making mobile health (mHealth) an attractive prospect. However, software developers often design without understanding the needs of ultimate users, solving non-existent problems. EULAR’s ‘Points to Consider’ for remote care specifies that interventions “should be developed in collaboration with all stakeholders including the healthcare team … and people with RMDs” as an overarching principle. This study sought to understand existing challenges for end-users, how technology might support care, and the perceived barriers.

Methods
Semi-structured interviews were devised collaboratively between rheumatologists and computer scientists, informed by discussions with an RA patient group. Key focus topics included daily life, flares, pain management, medications, clinic appointments, and perceived opportunities and barriers. People &gt;18 years old with a diagnosis of RA were recruited whilst awaiting appointments, & in the day unit at Mile End Hospital (Barts Health NHS Trust). Clinicians were recruited from multiple centres across London & South-East England. The study was registered (CMPS ID [43816]). Ethical approval was obtained through the Bloomsbury Research and Ethics Committee (19/LO/1345). Patient interviews were conducted by PC, Clinician interviews were conducted by AMB between October 2019-March 2020. Interviews were transcribed, and coded for themes using grounded theory techniques, identifying central themes. Coders (AMB & PC) utilised consensual coding, ensuring consistency.

Results
21 people with RA and 14 clinicians were interviewed. People with RA’s primary goal is to improve independence and quality and life, whereas clinicians primarily focus on remission. However, both groups identified consensual opportunities and barriers. Key themes with supporting quotes are detailed in table 1:

Conclusion
Opportunities for technology to improve care include: utilising remote monitoring to provide a broader picture of disease behaviour, improving access to care & co-ordinating care plans across primary and secondary care, improving the quality of disease education & empower people with RA to self-manage, the need for individualised care, and preservation of the therapeutic relationship when care is delivered remotely. Barriers can be sub-divided into patient, clinician, healthcare system, and technological.
Disclosure
A. MacBrayne: None. P. Curzon: None. H. Soyel: None. W. Marsh: None. N. Fenton: None. C. Pitzalis: None. F. Humby: None.
P150 The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis
Authors: Leask Andrew , Stratton Richard J , Xu Shiwen , Chitturi Pratyusha 
Published: April 2023

Abstract

Background/Aims
Scleroderma (systemic sclerosis, SSc) is an autoimmune inflammatory-fibrosis syndrome that damages the skin and internal organs and is considered a prototypic complex fibrotic disease. In SSc, persistently activated myofibroblasts are maintained by an excessive, autocrine mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit in SSc. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid plant-derivative celastrol has recently been identified as a YAP inhibitor; however, if celastrol can alleviate SSc fibrosis, and its underlying mechanism of action, is as yet unclear.

Methods
We cultured age-, sex-, and site-matched human dermal fibroblasts sampled from healthy individuals and patients with early onset (&lt;18 month after first diagnosis) diffuse cutaneous scleroderma (systemic sclerosis, dcSSc) and treated with or without transforming growth factor β1 (TGFβ1, 4ng/ml) in the presence or absence of celastrol (500nM). We also subjected C57BL6J mice to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol (28days, every day, 0.1U bleomycin, 1mg/kg celastrol). RNA expression was assessed using RNAseq and real-time polymerase chain reaction analysis. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining of tissue sections, and by using indirect immunofluorescence analysis with anti-alpha-smooth muscle actin (SMA) antibodies to detect myofibroblasts.

Results
In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein (N = 6, all p &lt; 0.01). Celastrol also alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients, including the overproduction of CCN2 and collagen (N = 3, p &lt; 0.05). Finally, in the bleomycin-induced model of SSc dermatopathology, celastrol inhibited skin thickness/collagen deposition in vivo and blocked nuclear localization of YAP in SMA-positive myofibroblasts (all N = 6, p &lt; 0.01).

Conclusion
Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway warrant further consideration as potential treatments for SSc skin fibrosis.
Disclosure
A. Leask: Grants/research support; CIHR, NSERC, Arthritis Society of Canada. R.J. Stratton: None. S. Xu: None. P. Chitturi: None.
P151 Prevalence and risk factors of osteoporosis in Indian systemic sclerosis patients
Authors: Tanna Dhaval , Ghosh Shounak , Telang Kaustubh , Ekbote Gayatri , Singal Vinay , Gupta Rajiva 
Published: April 2023

Abstract

Background/Aims
Systemic sclerosis (SSc) is a systemic autoimmune disease in which osteoporosis has been reported to be more prevalent than in healthy individuals. Bone loss is hypothesised to be related to vasculopathy in SSc, but the causative pathways are not very clear. This study was conducted to investigate the prevalence of osteoporosis in Indian patients with SSc and to assess its association with various disease-related characteristics.

Methods
This was a cross-sectional, case-control study performed in a 1,250 bedded tertiary care hospital. Between August 2017 and June 2019, all consecutive patients attending the outpatient and in-patient departments of the Department of Rheumatology & Clinical Immunology at our institute, classified as SSc as per the ACR/EULAR 2013 criteria, were included after taking their informed consent. Age and gender-matched healthy controls were included and all enrolled subjects were subjected to a dual energy X-ray absorptiometry (DEXA) scan. Demographic and clinical details of all patients were recorded. Osteoporosis was defined as per the WHO definition of a T score ≤ -2.5. The study was approved by the Institutional Review Board and the Institutional Ethics Committee.

Results
90 patients with SSc and 45 age and gender-matched healthy controls were included in the study. Confounding factors for bone health, like smoking or alcohol intake, the proportion of post-menopausal women, and past or family history of fragility fractures, were matched between the two groups. The prevalence of osteoporosis among SSc cases was significantly higher than in the healthy controls (34.4% vs. 6.6%, p &lt; 0.001). In univariate analysis, age, low body mass index (BMI), post-menopausal status, diffuse cutaneous phenotype, gastrointestinal involvement, digital ulcers, and pulmonary arterial hypertension were found to be significantly associated with osteoporosis. Multivariate analysis revealed that the presence of osteoporosis was significantly associated with lower BMI, post-menopausal status, and the presence of digital ulcers in patients. Interestingly, glucocorticoid use did not appear to increase the risk of osteoporosis in our cohort.

Conclusion
Patients with systemic sclerosis and digital ulcers, low BMI, or post-menopausal status are at high risk of developing osteoporosis and therefore should be screened for osteoporosis by DEXA scan to prevent unforeseen fracture-related morbidity and mortality. Glucocorticoids may not be the major culprit as evidenced by this study, while control of disease activity may lead to better bone health status.
Disclosure
D. Tanna: None. S. Ghosh: None. K. Telang: None. G. Ekbote: None. V. Singal: None. R. Gupta: None.
P154 Real-world audit of patients with idiopathic inflammatory myositis-related interstitial lung disease in a European population
Authors: Loganathan Aravinthan , Sturney Sharon , Foley Noeleen , Hartley Tom , Tansley Sarah 
Published: April 2023

Abstract

Background/Aims
The British Society for Rheumatology (BSR) has released guidelines for managing idiopathic inflammatory myositis (IIM). Our centre operates specialist clinics for scleroderma and lupus, but to date, IIM patients are seen in a general CTD clinic. As part of work to establish a dedicated myositis clinic, we collated data on 71 patients under active follow-up with myositis spectrum disease deemed appropriate for follow-up within a specialist clinic. We aimed to review patients diagnosed with IIM-ILD and review serological immune profile, screening practices for pulmonary involvement, findings on CT/pulmonary function tests (PFTs) and pharmacological management.

Methods
We performed a detailed retrospective review of the notes of suitable patients, identified using diagnostic codes attached to clinic letters.

Results
71 patients were identified: 14 with anti-synthetase syndrome (ARS), 21 with dermatomyositis (DM), 13 with polymyositis (PM), 3 with immune-mediated necrotising myopathy (IMNM) and 17 with overlap syndrome. 65% (46/70) of adult IIM patients were screened for pulmonary involvement. Screening practices of patients based on antibody profile and myositis subtype are further described in the table. 31% of patients (22/70) had IIM-ILD, of which 12 had ARS, 4 had PM, 1 had DM and 5 had overlap disease (2 PM/scleroderma, 1 DM/ARS, 1 DM/scleroderma and 1 scleroderma/ARS). 21/22 underwent PFTs; 53% of patients had active ILD over an average of 51.8 months. On imaging, 76.2% (16/22) had changes consistent with ILD. Ground glass change and reticulation were demonstrated in 50% of scans. In comparison, honeycombing and traction bronchiectasis was found in 22% and 44% of scans, respectively. A non-specific interstitial pneumonia (NSIP) pattern was described in 44% of scans, organising pneumonia (OP) pattern in 22%, and 17% had a mixed OP and NSIP pattern. 20/22 patients were prescribed high-dose steroids, csDMARD therapy or aggressive immunosuppression (cyclophosphamide or rituximab).

Conclusion
Our review demonstrates that 65% of patients with adult IIM were screened for ILD. NSIP and OP were the most common radiological appearances. Half of our cohort required aggressive immunosuppression, cyclophosphamide being the most commonly prescribed agent and mycophenolate being preferred for maintenance therapy. No patients were prescribed tacrolimus or ciclosporin. Despite treatment, 52% of patients had evidence of progressive disease on serial PFTs.
Disclosure
A. Loganathan: Grants/research support; Arthritis Australia. S. Sturney: None. N. Foley: None. T. Hartley: None. S. Tansley: None.
P158 Defining distinct fibroblast populations in systemic sclerosis skin using functional characterization and single-cell RNA sequencing
Authors: Clark Kristina E , Xu Shiwen , Ong Voon H , Buckley Christopher D , Denton Christopher 
Published: April 2023

Abstract

Background/Aims
Fibroblasts isolated by traditional explant culture from skin biopsies in systemic sclerosis (SSc) have a profibrotic and “migratory” phenotype. Single cell RNAseq (scRNAseq) studies suggest other fibroblast subpopulations may be important in SSc pathogenesis. We have isolated a second fibroblast population termed “resident” from whole skin in SSc. We used bulk and scRNAseq to further characterise these populations.

Methods
Forearm skin from dcSSc (n = 3) and HC (n = 3) was biopsied. “Migratory” fibroblasts were isolated by standard explant culture. The remaining biopsy fragments underwent collagenase digestion to yield a second “resident” fibroblast population. Functional characterization included 3-D collagen gel contraction, migratory scratch-wound assays and western blot comparing expression of pro-collagen I, CTGF and αSMA. Significant difference in gene expression was defined by fold change≥1.5, and adjusted p-value&lt;0.05. scRNAseq was performed on 12 SSc whole skin biopsies, and 3 HC, using the 10X Genomics platform.

Results
Both SSc fibroblast populations showed a fibrotic phenotype with overexpression of COL1, CTGF and αSMA compared to HC, but with reduced expression αSMA in resident compared to migratory SSc fibroblasts (p &lt; 0.05). RNAseq confirmed 1483 genes being significantly differentially expressed between the SSc fibroblast populations (Table 1). All four populations clustered separately on hierarchical clustering. 10 fibroblast clusters were identified using scRNAseq of whole skin. Of these, cluster 0 and 4 showed greater expression of COL10A1, and STC2 in keeping with migratory fibroblasts. Increased expression of CCL2, and EGR1 were seen in clusters 3 and 6, representing the resident fibroblast population. Gene set enrichment analysis (GSEA) confirmed concordance between KEGG pathway upregulation of the migratory and resident fibroblast clusters and bulk RNAseq analysis. Resident fibroblasts showed upregulation of complement and coagulation genes, and JAK/STAT signalling pathway. There was upregulation of glycolysis gluconeogenesis, and PPAR signalling in migratory fibroblasts. There was agreement in GSEA findings between relevant scRNAseq clusters and bulkRNAseq for resident and migratory subpopulations.

Conclusion
We have isolated for the first time two distinct profibrotic fibroblast populations from SSc skin with altered expression of key genes associated with SSc pathogenesis. Future work will define their role in SSc pathogenesis, potentially facilitating a more targeted treatment approach.
Disclosure
K.E. Clark: None. S. Xu: None. V.H. Ong: None. C.D. Buckley: None. C. Denton: None.