Anti-RA33 antibodies are present in a subset of patients with immune checkpoint inhibitor-induced inflammatory arthritis

Background Patients with inflammatory arthritis (IA) associated with immune checkpoint inhibitor (ICI) treatment for cancer are typically seronegative for anti-CCP antibodies and rheumatoid factor, but little is known about the presence of other autoantibodies described in early inflammatory arthritis in this patient population. We investigated the prevalence and characteristics of anti-RA33 antibodies in patients with ICI-induced IA. Methods Anti-RA33 ELISAs were performed on sera from four groups of patients: 79 with ICI-induced IA, 52 with rheumatoid arthritis (RA), 35 treated with ICIs without IA during follow-up, and 50 healthy controls. Anti-RA33 positivity and titer, clinical and demographic data were compared across groups. Results Anti-RA33 antibodies were found in 9/79 (11.4%) patients with ICI-induced IA but in 0/35 patients treated with ICIs who did not develop IA (0%; p=0.04). Of the 9 patients positive for anti-RA33, two had sera available from before ICI treatment; anti-RA33 antibodies were present in both pre-ICI treatment. In RA patients, 7.7% were positive for anti-RA33 antibodies as were 2% of healthy controls. In ICI-induced IA, anti-RA33 antibodies were associated with anti-CCP antibodies (p=0.001). We found no statistically significant differences in other clinical characteristics in those with and without anti-RA33 antibodies, but we observed trends toward anti-RA33 antibodies being more common in women and those receiving prior radiation therapy. Conclusions Anti-RA33 antibodies are present in a subset of patients with ICI-induced IA and may be a biomarker for developing IA. Additional studies evaluating serial samples before and after ICI treatment will further establish the temporal relationship of these antibodies to IA development.

A Bayesian network approach incorporating imputation of missing data enables exploratory analysis of complex causal biological relationships

Bayesian networks can be used to identify possible causal relationships between variables based on their conditional dependencies and independencies, which can be particularly useful in complex biological scenarios with many measured variables. Here we propose two improvements to an existing method for Bayesian network analysis, designed to increase the power to detect potential causal relationships between variables (including potentially a mixture of both discrete and continuous variables). Our first improvement relates to the treatment of missing data. When there is missing data, the standard approach is to remove every individual with any missing data before performing analysis. This can be wasteful and undesirable when there are many individuals with missing data, perhaps with only one or a few variables missing. This motivates the use of imputation. We present a new imputation method that uses a version of nearest neighbour imputation, whereby missing data from one individual is replaced with data from another individual, their nearest neighbour. For each individual with missing data, the subsets of variables to be used to select the nearest neighbour are chosen by sampling without replacement the complete data and estimating a best fit Bayesian network. We show that this approach leads to marked improvements in the recall and precision of directed edges in the final network identified, and we illustrate the approach through application to data from a recent study investigating the causal relationship between methylation and gene expression in early inflammatory arthritis patients. We also describe a second improvement in the form of a pseudo-Bayesian approach for upweighting certain network edges, which can be useful when there is prior evidence concerning their directions.

Exploring the macro-level, meso-level and micro-level barriers and facilitators to the provision of good quality early inflammatory arthritis (EIA) care in England and Wales

BackgroundEvidence from a national clinical audit of early inflammatory arthritis (EIA) shows considerable variability between hospitals in performance, unexplained by controlling for case-mix.ObjectiveTo explore the macro-level, meso-level and micro-level barriers and facilitators to the provision of good quality EIA care.MethodsA qualitative study within 16 purposively sampled rheumatology units across England and Wales. Quality was assessed in relation to 11 quality indicators based on clinical opinion, evidence and variability observed in the data. Data from semi-structured interviews with staff (1–5 from each unit, 56 in total) and an online questionnaire (n=14/16 units) were integrated and analysed using the framework method for thematic analysis using a combined inductive and deductive approach (underpinned by an evidence-based framework of healthcare team effectiveness), and constant comparison of data within and between units and its relationship with the quality criteria.FindingsQuality of care was influenced by an interplay between macro, meso and micro domains. The macro (eg, shared care arrangements and relationships with general practitioners) and meso (eg, managerial support and physical infrastructure) factors were found to act as crucial enablers of and barriers to higher quality service provision at the micro (team) level. These organisational factors directly influenced team structure and function, and thereby EIA care quality.ConclusionsVariability in quality of EIA care is associated with an interplay between macro, meso and micro service features. Tackling macro and meso barriers is likely to have a significant impact on quality of EIA service, and ultimately patient experience and outcomes.

POS0959 DIAGNOSTIC DELAY IN AXIAL SPONDYLOARTHRITIS: RESULTS FROM THE NATIONAL EARLY INFLAMMATORY ARTHRITIS AUDIT

Background:Diagnostic delay is a significant problem in axial spondyloarthritis (axSpA), and there is a growing body of evidence showing that delayed axSpA diagnosis is associated with worse clinical, humanistic and economic outcomes.1 International guidelines have been published to inform referral pathways and improve standards of care for patients with axSpA.2,3Objectives:To describe the sociodemographic and clinical characteristics of newly-referred patients with axSpA in England and Wales in the National Early Inflammatory Arthritis Audit (NEIAA), with rheumatoid arthritis (RA) and mechanical back pain (MBP) as comparators.Methods:The NEIAA captures data on all new patients over the age of 16 referred with suspected inflammatory arthritis to rheumatology departments in England and Wales.4 We describe baseline sociodemographic and clinical characteristics of axSpA patients (n=784) recruited to the NEIAA between May 2018 and March 2020, compared with RA (n=9,270) and MBP (n=370) during the same period.Results:Symptom duration prior to initial rheumatology assessment was significantly longer in axSpA than RA patients (p<0.001), and non-significantly longer in axSpA than MBP patients (p=0.062): 79.7% of axSpA patients had symptom durations of >6 months, compared to 33.7% of RA patients and 76.0% of MBP patients; 32.6% of axSpA patients had symptom durations of >5 years, compared to 3.5% of RA patients and 24.6% of MBP patients (Figure 1A). Following referral, median time to initial rheumatology assessment was longer for axSpA than RA patients (36 vs. 24 days; p<0.001), and similar to MBP patients (39 days; p=0.30). The proportion of axSpA patients assessed within 3 weeks of referral increased from 26.7% in May 2018 to 34.7% in March 2020; compared to an increase from 38.2% to 54.5% for RA patients (Figure 1B). A large majority of axSpA referrals originated from primary care (72.4%) or musculoskeletal triage services (14.1%), with relatively few referrals from gastroenterology (1.9%), ophthalmology (1.4%) or dermatology (0.4%).Of the subset of patients with peripheral arthritis requiring EIA pathway follow-up, fewer axSpA than RA patients had disease education provided (77.5% vs. 97.8%; p<0.001), and RA patients reported a better understanding of their condition (p<0.001). HAQ-DI scores were lower at baseline in axSpA EIA patients than RA EIA patients (0.8 vs 1.1, respectively; p=0.004), whereas baseline Musculoskeletal Health Questionnaire (MSK-HQ) scores were similar (25 vs. 24, respectively; p=0.49). The burden of disease was substantial across the 14 domains comprising MSK-HQ in both axSpA and RA (Figure 1C).Conclusion:We have shown that diagnostic delay remains a major challenge in axSpA, despite improved disease understanding and updated referral guidelines. Patient education is an unmet need in axSpA, highlighting the need for specialist clinics. MSK-HQ scores demonstrated that the functional impact of axSpA is no less than for RA, whereas HAQ-DI may underrepresent disability in axSpA.References:[1]Yi E, Ahuja A, Rajput T, George AT, Park Y. Clinical, economic, and humanistic burden associated with delayed diagnosis of axial spondyloarthritis: a systematic review. Rheumatol Ther. 2020;7:65-87.[2]NICE. Spondyloarthritis in over 16s: diagnosis and management. 2017.[3]van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-91.[4]British Society for Rheumatology. National Early Inflammatory Arthritis Audit (NEIAA) Second Annual Report. 2021.Acknowledgements:The National Early Inflammatory Arthritis Audit is commissioned by the Healthcare Quality Improvement Partnership, funded by NHS England and Improvement, and the Welsh Government, and carried out by the British Society for Rheumatology, King’s College London and Net Solving.Disclosure of Interests:Mark Russell Grant/research support from: UCB, Pfizer, Fiona Coath: None declared, Mark Yates Grant/research support from: UCB, Abbvie, Katie Bechman: None declared, Sam Norton: None declared, James Galloway Grant/research support from: Abbvie, Celgene, Chugai, Gilead, Janssen, Lilly, Pfizer, Roche, UCB, Jo Ledingham: None declared, Raj Sengupta Grant/research support from: AbbVie, Biogen, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Karl Gaffney Grant/research support from: AbbVie, Biogen, Cellgene, Celltrion, Janssen, Lilly, Novartis, Pfizer, Roche, UCB.

POS0395 ANTI-ACETYLATED PROTEIN ANTIBODIES IN RHEUMATOID ARTHRITIS (RA): CLUES FOR THE STARTING POINT OF AUTOANTIBODY RESPONSES IN RA

Background:Rheumatoid arthritis (RA) is characterized by autoantibodies such as rheumatoid factor (RF) and anti-modified protein autoantibodies (AMPAs) like anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein antibodies (anti-CarP). Recently, another AMPA: anti-acetylated protein antibodies (AAPA) have been found in RA patients [1]. The prevalence of AAPA antibodies and their isotypes have yet to be determined. Since isotype profiles reflect the breadth of an immune response, the prevalence of AAPA isotypes in arthritis patients with and without RA can help to understand the relevance of this autoantibody response in RA.Objectives:To describe the prevalence of AAPA isotypes in arthritis patients with and without RA.Methods:In 650 RA patients fulfilling the 1987 RA criteria and 555 non-RA arthritis patients from the Leiden Early Arthritis Cohort, baseline serum samples were screened by ELISA for IgG, IgM and IgA to an acetylated- and control peptide that was based upon the CCP-2 backbone. The cutoff for positivity was based on 80 controls (mean + 2SD). A sample was considered positive if it was above the cutoff and was 0.1 optical density higher on the acetylated peptide than on the control peptide.Results:AAPA IgG was found in 36% of RA patients versus 6.7% of non-RA arthritis patients (figure 1a). Within RA patients, AAPA IgG antibodies were mostly present in the ACPA-(CCP-2) positive group (64% in ACPA-positive, compared to 5% in ACPA-negative). Levels of AAPA IgG and IgA were higher in RA patients than in healthy controls and non-RA arthritis patients (figure 1b), however, surprisingly, no difference in levels was found for IgM.When isotype profiles in AAPA- positive arthritis patients were compared, patients with RA were more often positive for two or more isotypes then patients without RA, and thus displayed considerably more overlap in AAPA isotypes compared to non-RA patients (table 1). Intriguingly, IgM AAPA was the most prevalent isotype in non-RA patients, versus IgG in RA patients.Table 1.Anti-acetylated protein antibody (AAPA) isotype overlap in AAPA positive patients.AAPA isotypeRA patients (=310) n (%)Non-RA arthritis patients (n=106) n (%)IgG+IgM-IgA-115 (37.1)28 (5.1)IgG-IgM+IgA-52 (16.8)48 (8.7)IgG-IgM-IgA+14 (4.5)13 (2.3)IgG+IgM+IgA-24 (7.7)3 (0.5)IgG+IgM-IgA+37 (11.9)4 (0.7)IgG-IgM+IgA+9 (2.9)8 (1.4)IgG+IgM+IgA+59 (19.0)2 (0.4)AAPA: anti-acetylated protein antibodies, RA: rheumatoid arthritisConclusion:AAPA are detected in one third of RA patients, and mainly in the ACPA-positive subgroup. The predominance of IgM AAPA in non-RA arthritis patients and healthy controls suggests that healthy persons can develop AAPA IgM without the development of RA. These results also suggest that in healthy individuals, AAPA responses can occur, but do not mature past the IgM-stage, while in RA patients, the AAPA-response does mature and might form a “starting point” for development of other AMPA leading to the concurrent present of several AMPA in disease.References:[1]Juarez, M., et al., Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann Rheum Dis, 2016. 75(6): p. 1099-107.Disclosure of Interests:None declared

TCRβ Sequencing Reveals Spatial and Temporal Evolution of Clonal CD4 T Cell Responses in a Breach of Tolerance Model of Inflammatory Arthritis

Effective tolerogenic intervention in Rheumatoid Arthritis (RA) will rely upon understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of endogenous CD4 T cell infiltrates in early inflammatory arthritis was assessed to monitor evolution of the TCR repertoire in the inflamed joint and associated lymph node (LN). Mouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate early and late phases of RA. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and LNs were analysed using flow cytometry and TCRβ sequencing. TCR repertoires from inflamed late phase LNs displayed increased clonality and diversity compared to early phase LNs, while inflamed joints remained similar with time. Repertoires from late phase LNs accumulated clones with a diverse range of TRBV genes, while inflamed joints at both phases contained clones expressing similar TRBV genes. Repertoires from LNs and joints at the late phase displayed reduced CDR3β sequence overlap compared to the early disease phase, however the most abundant clones in LNs accumulate in the joint at the later phase. The results indicate CD4 T cell repertoire clonality and diversity broadens with progression of inflammatory arthritis and is first reflected in LNs before mirroring in the joint. These observations imply that antigen specific tolerogenic therapies could be more effective if targeted at earlier phases of disease when CD4 T cell clonality is least diverse.

P016 When and how to deliver advice about self-management: local observations from the National Early Inflammatory Arthritis Audit

Background/Aims The National Early Inflammatory Arthritis Audit (NEIAA) provides the opportunity for rheumatology services to benchmark the care they provide against NICE quality standards (QS) 33. During the first year of the audit our focus, after being identified as an outlier, was on improving performance against QS2 and specifically reducing waiting times. This project assessed compliance against QS4: patients with rheumatoid arthritis (RA) are offered educational and self-management activities within 1 month of diagnosis. Methods Data submitted to the NEIAA online tool during the second year of the audit were downloaded for analysis. Results were presented initially to our National RA Society (NRAS) Patient Support Group and then together with feedback from the patients, to the Rheumatology Multi-Disciplinary Team. Driver diagrams were developed and areas for improvement identified. Results In total, 268 patients were recruited to the audit in year 2; 73 (27%) had confirmed RA and were included in this analysis. Follow-up data at 3 months was available for 56 patients (77%). Characteristics were: mean age 58 years (range: 19-88), 47 (64%) female, 34 (47%) working and 11 (15%) smoked. Forty-one patients (56%) started DMARD therapy within 6 weeks of referral. All patients with RA received written information at baseline about their condition. However, only 39 patients (71%) were documented to have been provided with advice about self-management at their 3-month follow-up. Feedback from the NRAS Group highlighted a number of important considerations. Firstly, that information about self-management needs to be given to the patient at the right time. Patients need to be ready to take advice on board and to have come to terms with their diagnosis. For many, trying to do this in the first 3 months of diagnosis was felt too soon. Information needs to be made available in different formats and tailored to the individual. Patients valued speaking to someone with a lived experience and felt this was more powerful than speaking to a healthcare professional to understand about self-management. Driver diagrams highlighted areas for improvement which included the importance of the team agreeing what is meant by self-management, using a patient activation measure to determine if the patient is ready to take on board this information, exploring different formats of delivery and utilising expert patients. Conclusion The NEIAA has again enabled the team to identify further areas for improvement. Involving patients in the discussion has provided a valuable insight into how we look to support our patients to live with their condition. It has also led us to question whether the QS is right to support that self-management advice is offered to patients within 1 month of diagnosis. Disclosure E. MacPhie: Other; EM is the secretary of the North West Rheumatology Club, these regional meetings have been funding by an unrestricted educational grant from UCB and are now sponsored by Abbvie. L. Ashcroft: None. J. Brazendale: None. N. Foreman: None. S. Gilbert: None. C. Greenall: None. S. Horton: None. I. Lewis: None. A. Madan: None. C. Rao: None. S. Fish: None.

P017 Out of outlier status: local observations from the National Early Inflammatory Arthritis Audit

Background/Aims The National Early Inflammatory Arthritis Audit (NEIAA) provides a powerful lever for driving up quality. Rheumatology services benchmark care against NICE quality standards (QS) 33. Notifications are sent out quarterly to Trusts at risk of being an outlier and outliers are identified in the annual report. After being named as an outlier, this project describes our journey to improve compliance against QS2 (patients are seen in a rheumatology clinic within 3 weeks of referral and QS3 (patients with rheumatoid arthritis (RA) are started on DMARDs within 6 weeks of referral). Methods Data submitted to the NEIAA online tool during year one were downloaded for analysis. Results were presented to the Rheumatology Multi-Disciplinary Team, the patient pathway was mapped, driver diagrams were developed by the team and areas for improvement identified and changes implemented. Data from year two were downloaded for comparison. Results In total 530 patients were recruited to the audit: 262 in year 1 and 268 in year 2. 77 (29%) in year 1 and 73 (27%) in year 2 had confirmed RA and were included in this analysis. All patients had a baseline form completed, and 61 (86%) and 56 (77%) had a 3-month follow-up form completed for year 1 and 2, respectively. The demographics were very similar for years 1 and 2. In year 1, 10% of all patients were seen within 3 weeks of being referred and 7% in the RA cohort started DMARD therapy within 6 weeks of referral. This compared to 54% and 56%, respectively, in year 2. Changes implemented relating to QS2 included referral guidelines for primary care, prompts when requesting rheumatoid factor and CCP antibodies and changes to the wording of antibody reports, increased triage capacity, simplifying the booking process and increased new appointment capacity (additional consultant, upskilling extended scope practitioner). QS3 changes implemented included increasing drug education and monitoring clinic capacity and improved sign-posting to National Rheumatoid Arthritis Society. Initial combination therapy was more prevalent in sero-positive patients and those with a high DAS28 during both years. In year 1, disease activity at baseline vs. 3 months was: remission/low disease activity in 8% vs. 54%, moderate in 45% vs. 39% and high in 47% vs. 7%. In year 2, rates at baseline vs. 3 months were: remission/low disease activity 12% vs. 69%, moderate in 60% vs. 25% and high in 28% vs. 6%. Conclusion Significant changes have been made which have resulted in an improvement in performance against QS2 and 3. Disease activity at baseline was lower, potentially as a result of seeing patients sooner and this has resulted in better outcomes for patients at 3 months. Ongoing data collection will allow the team to determine outcomes at 12 months. Disclosure E. MacPhie: Other; EM is the secretary of the North West Rheumatology Club, these regional meetings have been funding by an unrestricted educational grant from UCB and are now sponsored by Abbvie. L. Ashcroft: None. J. Brazendale: None. N. Foreman: None. S. Gilbert: None. C. Greenall: None. S. Horton: None. I. Lewis: None. A. Madan: None. C. Rao: None. S. Fish: None.