bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution theories for genetic line of least resistance and evolvability measures
Authors: Watanabe Junya 
Published: April 2024

Abstract
Quantitative genetic theory on multivariate character evolution predicts that a population’s response to directional selection is biased towards the major axis of the genetic covariance matrix G—the so-called genetic line of least resistance. Inferences on the genetic constraints in this sense have traditionally been made by measuring the angle of deviation of evolutionary trajectories from the major axis or, more recently, by calculating the amount of genetic variance—the Hansen–Houle evolvability—available along the trajectories. However, there have not been clear practical guidelines on how these quantities can be interpreted, especially in a high-dimensional space. This study summarizes pertinent distribution theories for relevant quantities, pointing out that they can be written as ratios of quadratic forms in evolutionary trajectory vectors by taking G as a parameter. For example, a beta distribution with appropriate parameters can be used as a null distribution for the squared cosine of the angle of deviation from a major axis or subspace. More general cases can be handled with the probability distribution of ratios of quadratic forms in normal variables. Apart from its use in hypothesis testing, this latter approach could potentially be used as a heuristic tool for looking into various selection scenarios, like directional and/or correlated selection, as parameterized with the mean and covariance of selection gradients.
OA09 Significant association between disease duration in axial spondyloarthritis and the occurrence of uveitis and inflammatory bowel disease, with no such association found for psoriasis
Authors: Dinneen Brona , Kenyon Marcus , O'Shea Finbar 
Published: April 2024

Abstract

Background/Aims
Axial spondyloarthritis is a chronic inflammatory condition primarily impacting the spine and sacroiliac joints. In addition to spinal inflammation and peripheral symptoms, it frequently presents with extra-musculoskeletal manifestations such as inflammatory bowel disease, psoriasis, and anterior uveitis, collectively adding to the overall disease burden. Although existing research has explored the heightened risk of ophthalmological manifestations with prolonged disease duration, there is a paucity of literature examining the association between disease duration in axial spondyloarthritis and the onset of inflammatory bowel disease and psoriasis. Aim: To investigate the relationship between axial spondyloarthritis disease duration and the development of extra-musculoskeletal manifestations.

Methods
This is a retrospective cohort study with data obtained from the Ankylosing Spondylitis Registry of Ireland (ASRI), which is a large cross-sectional, multicentre cohort study. Using both univariate and multivariate regression analyses, we examined the relationship between axial spondyloarthritis disease duration and extra musculoskeletal manifestations. In the multivariate analysis, several covariates including gender, body mass index, smoking, and HLA-B27 status were considered to account for their potential influence on the observed associations.

Results
Demographic details were available for 912 patients included at the time of analysis. The median disease duration in years for our cohort was 16. Table 1 presents relevant general characteristics of the ASRI cohort and the results of our regression analysis. Uveitis exhibited a highly significant association (P &lt; 0.001) with AxSpA duration in both univariate and multivariate analyses, even after accounting for covariates. Inflammatory bowel disease also showed a significant association with AxSpA duration in both univariate and multivariate analyses (P &lt; 0.003). In our analysis, psoriasis showed no significant relationship with AxSpA disease duration in both univariate (P = 0.298) and multivariate analyses (P1 = 0.249).

Conclusion
Our study, using a large data set, reveals distinct patterns of association between axial spondyloarthritis disease duration and inflammatory bowel disease and uveitis. Conversely, psoriasis demonstrates no significant link to disease duration when considering confounding factors. Clinically, these insights are crucial for tailored management strategies, emphasising the need for improved diagnostic time and multidisciplinary care to address the diverse manifestations of AxSpA and optimise patient outcomes.

Disclosure
B. Dinneen: None. M. Kenyon: None. F. O'Shea: None.
OA22 Pregnancy in connective tissue diseases: a 30 year follow-up study of 465 pregnancies from a Spanish monocentric registry
Authors: Santos Cristiana Sieiro , García Paula Pérez , Ordas Martínez Jose , Castro Carolina Álvarez , Díez Álvarez Elvira 
Published: April 2024

Abstract

Background/Aims
Pregnancy in patients with connective tissue diseases (CTDs) are known to be at high risk for the occurrence of adverse pregnancy outcomes. We aimed to evaluate pregnancy outcomes in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS) and undifferentiated connective tissue disease (UCTD).

Methods
A retrospective and descriptive study was conducted from 1990 to 2020. All data were collected from the medical records of women of childbearing age with SLE, SSc, SS and UTCD enrolled in our clinic at the time of their pregnancy and childbirth. The obstetric, maternal and fetal outcomes were collected and compared regarding diagnosis and adverse outcomes.

Results
The study group included 295 patients: 125 patients (42%) with SLE; 50 patients (17%) with SSc; 80 patients (27%) with pSS; 40 patients (14%) with UCTD. A total of 465 pregnancies were registered. The mean age at delivery was 31.5±8.5 years and the mean duration of disease was 7.2±5.6 years. Pregnancy loss occurred in 21% of patients, live births in 66% of pregnancies, preterm delivery in 8%, postpartum haemorrhage in 6%, preeclampsia in 5%, placental abnormalities in 4%, ectopic pregnancy in 3%, and premature rupture of membranes in 2%. Treatment with hydroxychloroquine (HCQ) was received in 115 pregnancies in SLE (59%), 21 pregnancies in SSc (24%) 62 pregnancies in pSS (52%) and 32 pregnancies in UCTD (49%). Exposure to corticosteroids and biologics during pregnancy was 23 (18.4%), 6 (12%), 15 (19%) and 3 (7.5%), respectively. Patients with SLE had a higher risk of fetal morbidity, including abortion (p = 0.03), mean abortion rate (p = 0.03), preeclampsia (p = 0.04), ectopic pregnancy (p = 0.03), preterm delivery (p = 0.02) and postpartum haemorrhage (p = 0.01) than patients without SLE. The multivariate model found an association between unfavourable pregnancy outcomes and disease activity (OR 2.4; 95% CI 1.3-7.2; p 0.003), whilst HCQ during pregnancy (OR 0.23; 95% CI 0.03-0.82) had a protective effect.

Conclusion
66% of pregnancies in patients with autoimmune diseases resulted in live births. Patients with SLE had higher rates of fetal and maternal morbidity than SSc, pSS and UCTD. Disease activity was associated with unfavourable pregnancy outcomes. Exposure to HCQ had a protective effect during pregnancy.

Disclosure
C. Sieiro Santos: None. P. Pérez García: None. J. Ordas Martínez: None. C. Álvarez Castro: None. E. Díez Álvarez: None.
OA27 Molecular divergences in CD4+ T Cells between early and refractory rheumatoid arthritis
Authors: Smith Samantha L , Rossi Stefano , Shukla Rudresh , Tan Yvonne , Ariff Amirah , Lazar Ilinca , Patel Khadijah , Yap Chuan F , Nair Nisha , Eyre Steve , Buch Maya H , Buch Maya H , Martin Paul , Orozco Gisela 
Published: April 2024

Abstract

Background/Aims
Up to 21% of rheumatoid arthritis (RA) patients remain refractory to available treatments. This represents a clinical challenge due to the lack of efficacious alternatives for refractory RA (rRA) patients. Although CD4+ T cells are paramount in RA pathogenesis, a comprehensive understanding of their roles in rRA versus non-refractory RA has not been characterised. The aim of this study is to dissect the molecular differences in CD4+ T cells across these patient sub-groups and identify novel mechanisms driving rRA, which may inform tailored therapeutic strategies, using single cell multiomic analysis.

Methods
Primary CD4+ T-cells were isolated from PBMCs obtained from 3 rRA patients (defined as per EULAR definition of difficult-to-treat RA) and 3 treatment-naïve, early RA (ERA) patients, all seropositive with active disease (DAS28-ESR &gt; 3.2), collected as part of the PRECISE-RA programme. Following nuclei extraction, the 10x Genomics Multiome ATAC + Gene Expression assay was used to simultaneously determine the transcriptional and chromatin landscapes from individual cells.

Results
Patient characteristics are reported in Table 1. 8,215 T-cells cells were clustered into 11 distinct cell states, which showed a trend towards diminished Tregs and modulated effector memory (TEM)/Th17 phenotype expressions in rRA compared to ERA patients. In ERA, expression of INPP4B, pivotal for cell growth and survival, was upregulated within naïve CD4+ T-cell subsets. ITGA4, crucial in leukocyte migration and adhesion, was elevated within a subset of naïve CD4+ T cells in early RA. ZEB2 exhibited increased expression within CD4 TEM/Th17 phenotype cells, potentially implicating divergent cellular differentiation, and migratory pathways within early RA contexts. Next, we utilised the multiomic nature of the data to functionally annotate GWAS variants, by creating peak-gene maps and overlaying RA risk SNPs. For example, an RA susceptibility SNP mapping to an intron of ANKRD55, rs7731626, was linked to the novel RA causal gene IL6ST. Furthermore, the RA SNP rs71508903, previously assigned to the ARID5B gene, was linked to the RTKN2 promoter, elucidating potential avenues for further exploration into RA pathogenesis.

Conclusion
These findings, to be validated in a larger cohort, suggest distinct biological mechanisms driving rRA and may help identify novel biomarkers and therapeutic avenues.

Disclosure
S.L. Smith: None. S. Rossi: None. R. Shukla: None. Y. Tan: None. A. Ariff: None. I. Lazar: None. K. Patel: None. C.F. Yap: None. N. Nair: None. S. Eyre: None. M.H. Buch: None. M.H. Buch: None. P. Martin: None. G. Orozco: None.
OA40 Clinical and psychological factors associated with adherence based on a patient self-reported questionnaire: results from the biologics in rheumatoid arthritis genetics and genomics study syndicate (BRAGGS) cohort
Authors: Chong Timothy K Y , Nair Nisha , Morgan Ann W , Isaacs John D , Wilson Anthony G , Hyrich Kimme L , Plant Darren , Barton Anne 
Published: April 2024

Abstract

Background/Aims
To explore the relationship of clinical and psychological factors with adherence based on a patient self-reported questionnaire from a prospective longitudinal study of patients receiving TNFi biologic treatment for rheumatoid arthritis, recruited since 2008.

Methods
Analysis of data collected from a prospective longitudinal UK study (Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate [BRAGGSS]) of patients with moderate to severe RA commencing TNFi biologic treatment. Clinical data including Disease Activity Score-28 (DAS28), serological status (Rheumatoid Factor positivity) and body mass index (BMI) were collected. Patients also completed self-reported questionnaires, the health assessment questionnaire (HAQ), hospital anxiety and depression scale (HAD), beliefs about medicine questionnaire (BMQ), brief illness perception score (B-IPQ) and a self-reported adherence questionnaire. Adherence was defined as any deviation from prescribed medication regime such as altering the dose, forgetting a dose, stopping treatment, missing a dose, and taking less than instructed. Associations between demographic and psychological variables and adherence were evaluated using regression models and a multivariable logistic regression model was used to further evaluate associations, controlling for BMI.

Results
1,513 patients (75.7% female, age 58.1 [IQR 16.0], disease duration 9.6 ± 9.6 years and pre-treatment DAS28 scores 5.7 ± 0.8) were included. 70% of patients self-reported adherence to their medication. When comparing the different TNFi treatments, etanercept had the lowest levels of adherence at the 3 and 6 month time-points. Adherence was higher in those with older age (β = 0.03, p&lt; 0.01), higher baseline CRP levels (β = 0.01, p= 0.03) and higher necessity beliefs (β = 0.04, p= 0.03). Adherence was lower in those with higher tender joint counts at baseline (β=-0.03, p= 0.04) and 3 months (β = 0.03, p= 0.02) (Table I). These associations persisted after controlling for the effects of BMI using a multivariable logistic model.

Conclusion
Self-reported adherence was 70% in this BRAGGS population. Factors associated with non-adherence included higher tender joint counts and lower necessity beliefs pre-treatment, which may allow targeting of interventions to optimise adherence in these groups.

Disclosure
T.K.Y. Chong: None. N. Nair: None. A.W. Morgan: None. J.D. Isaacs: None. A.G. Wilson: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; K.H has grants from BMS and Pfizer. D. Plant: None. A. Barton: Grants/research support; A.B has received funding/speaker fees from BMS, Pfizer and Galapagos.
P003 A fast track giant cell arteritis pathway incorporating ultrasonography improves service provision in a District General Hospital
Authors: Ioannidis Diomidis , Premraj Sara , Ntatsaki Eleana 
Published: April 2024

Abstract

Background/Aims
Giant cell arteritis (GCA) is the most common form of adult vasculitis with comorbidities including blindness. Early identification and initiation of treatment is therefore essential. The 2020 BSR guideline suggests specialist review within three days of suspected GCA. In Ipswich Hospital, there was previously no universal referral pathway for GCA. Patients were referred to the acute medicine, A&E, rheumatology or ophthalmology clinics. An audit in 2018 over 18 months highlighted a significant delay in specialist reviews. In 2021 we designed a rapid access referral pathway for direct specialist review (protected one-stop slots in rheumatology or ophthalmology), including the use of a dedicated score for assessing the risk for GCA (GCAPS) and vascular ultrasonography in specialist clinics. Our aims for this quality improvement project were to: 1) Audit referral times for suspected GCA patients 2) Optimise the percentage of suspected GCA cases receiving a confirmatory test, notably ultrasound or temporary artery biopsy.

Methods
We audited the new GCA referrals from January 2022 to June 2023, and compared to the 2018 data. Data were retrospectively collected from electronic health records.

Results
44 patients were included (women=29, mean age=68). In 2023, 89% of patients were seen within three days, compared to 47% previously. In 2023, patients were reviewed within a median of two days by a specialist compared to 19 in 2018. Finally, 100% of our patients received a diagnostic test, compared to 79% previously (table 1). A total of 34% of new referrals were diagnosed as GCA. 40 patients had an ultrasound which was positive in 27%, equivocal in 25% and negative in 48%. For the remaining four patients, GCA was excluded without imaging tests/biopsy. 17 patients had biopsy, with 24% being positive for GCA. 52% of referred cases had high GCAPs score and 32% normal inflammatory markers.

Conclusion
Our fast-track referral pathway facilitated an earlier review for our patients. These results indicate the enhanced safety afforded for suspected GCA patients via a dedicated Fast Track GCA assessment clinic with access to ultrasonography. This also led to a significant reduction in the number of temporal artery biopsies required.

Disclosure
D. Ioannidis: None. S. Premraj: None. E. Ntatsaki: None.
P012 Health inequalities in the diagnosis and treatment of rheumatoid arthritis
Authors: Jeyaratnam Sangeeta , Fish Sarah , Horton Sarah , Madan Ayesha , Rao Chandini , MacPhie Elizabeth 
Published: April 2024

Abstract

Background/Aims
Patients with chronic diseases, such as rheumatoid arthritis (RA), from socially deprived backgrounds are known to have more severe disease, comorbidity and higher mortality rates. This study used National Early Inflammatory Arthritis Audit (NEIAA) data submitted by Lancashire and South Cumbria Foundation Trust to ascertain if social deprivation influences time to diagnosis and treatment escalation onto a high-cost drug (HCD).

Methods
Patients diagnosed with an inflammatory arthritis were recruited to NEIAA over a five-year period (May 2018 to March 2023). Information on demographics, patient postcodes, duration of symptoms prior to referral, GP referral time and rheumatology waiting time were analysed. Index of Multiple Deprivation (IMD) was derived from patient postcodes and patients divided into three groups based on IMD deciles. Patients with deciles 1-3 were grouped as most deprived, deciles 4-6 as middle and deciles 7-10 as least deprived. A case note review of a subgroup of patients who had been on treatment for 2-5 years was undertaken to investigate whether IMD decile was associated with treatment escalation onto a HCD. Data were analysed using descriptive and inferential statistics on Stata. Results were adjusted for confounders including age and gender.

Results
A total of 265 patients with RA were included, mean age 60 years, 63% female and 10% from ethnic minority groups. There were 31%, 25% and 44% in the most, middle and least deprived groups respectively. There was a higher proportion of patients from minority ethnic backgrounds in the most deprived group (most 21% vs least 3%). Symptom duration at time of presentation to the GP was greater than 3 months in 57% vs 48% of patients in the most and least deprived groups, respectively. Median was used to compare the GP referral times and rheumatology waiting times as there were outliers in the dataset. The most deprived group had longer GP referral times (most 16 days vs least 7 days); however, median rheumatology waiting time was similar across the three groups (most, middle and least deprived 27, 24 and 25 days respectively). There was no difference in escalation onto a HCD across the three groups.

Conclusion
Patients from the most deprived areas presented later and took longer to be referred. However, time to being seen in the rheumatology clinic and escalation onto a HCD was not found to be associated with social deprivation. Exploring this further on a national level will help understand if social deprivation is influencing care elsewhere. This work supports the need to focus more resource on raising public awareness in more deprived areas.

Disclosure
S. Jeyaratnam: None. S. Fish: None. S. Horton: None. A. Madan: None. C. Rao: None. E. MacPhie: None.
P038 Measuring social engagement in rheumatic and musculoskeletal diseases
Authors: Maciver Alison , Macfarlane Gary , Hollick Rosemary J 
Published: April 2024

Abstract

Background/Aims
Rheumatic and musculoskeletal diseases (RMDs) result in reduced social well-being and social engagement (SE). Despite being an important outcome for patients, SE is rarely measured in studies or clinical practice. Furthermore, social media and COVID-19 has changed how we interact with society. We aimed to evaluate existing SE measures used in RMD populations.

Methods
A systematic review of the qualitative literature and thematic analysis identified key impacts of RMDs and associated treatments on SE [unrestricted date -February 2023]. A systematic review of the quantitative literature [unrestricted date-February 2022] identified existing SE measures validated for use within RMDs, their constructs and compared these to themes identified from the qualitative literature.

Results
From 2601 records screened, we identified 30 eligible qualitative papers. Thematic analysis highlighted barriers and facilitators of SE in RMDs:. Barriers to SE included: 1) Direct effects of RMDs 2) Practicalities of undertaking SE 3) Social networks and roles. Facilitators of SE included: 1) Benefits of SE 2) Resilience & Acceptance 3) Activity Adjustment. From 7772 records screened we identified 15 specific SE measures validated in RMD populations. These measures focused on measuring frequency, satisfaction, difficulty, and modification of SE. Table 1 shows how many of the existing SE measures validated for use in RMDs identified in the quantitative systematic review measure the key impacts of RMDs on SE as identified in the qualitative thematic analysis.

Conclusion
Existing measures of SE do not assess the wide range of impacts identified as important to patients. There is a need for a new SE measure to inform interventions to improve health and social outcomes for people with RMDs. Focus groups involving individuals with RMDs, and key stakeholders are planned to present the findings from the systematic reviews and facilitate discussion to help inform development of a new measure of SE.

Disclosure
A. Maciver: None. G. Macfarlane: None. R.J. Hollick: None.
P040 Obesity and rheumatoid arthritis among individuals with low education
Authors: Khubchandani Jagdish , Banerjee Sri 
Published: April 2024

Abstract

Background/Aims
Poor education is connected to many diseases including cardiovascular diseases (CVD) and some CVD-related risk factors such as obesity. However, precisely how this relationship occurs is unknown. In this research we will be exploring how the connection between obesity and overall mortality is modified by rheumatoid arthritis (RA).

Methods
Our study was conducted on participants that were aged 20 years or older living in the United States with a education level of only some high school. We assessed RA status by using the arthritis question in the National Health and Nutrition Examination Survey (NHANES) survey conducted by the National Center for Health Statistics (NCHS) for the years of 1999 to 2010 with mortality follow-up to December 2019. We determined obesity by calculating BMI and setting a cutpoint at 30 kg/m2. Education level was determined through self-reported data. Chronic Kidney Disease was determined using the Cockcroft-Gault equation. Prospective analysis was performed using complex samples Cox regression with adjustment for known confounders to determine the relationship of obesity and mortality, and if RA has an overall relationship in those with low education.

Results
Among individuals with low education and RA, percent mortality was 32.3% among males and 32.6% among females with mean follow-up of 9.3 years. For overall mortality, the age and sex-adjusted hazard ratio (HR) for obesity was 1.18 (95% confidence interval [CI], 1.05-1.34 p = 0.01). The adjusted HR was elevated, 1.56 (CI 1.06-2.32, p = 0.03), among people with obesity who also had RA but close to 1.0 (1.21 CI 0.99-1.47, p = 0.06) among individuals with obesity who had no RA, after adjusting for medical (chronic obstructive pulmonary disease, history of cancer, cardiovascular disease, chronic kidney disease, and diabetes) and demographic risk factors (poverty-income-ratio, age, military service, citizenship, and gender).

Conclusion
We found that among individuals with low education, not only does obesity lead to 18% higher overall mortality but also RA occurrence impacts the relationship between obesity and overall mortality even after controlling for potential confounders. Education and health literacy are especially important in the preventing and treating RA especially in those who have obesity. With cardiovascular disease having the highest rate of mortality, risk factors for CVD such as obesity must be prevented.

Disclosure
J. Khubchandani: None. S. Banerjee: None.