Biologics Register Research Articles

OA31 Successes and challenges in harmonising 4 national Juvenile Idiopathic Arthritis cohorts: an example from CLUSTER consortium

Introduction/BackgroundThe CLUSTER consortium aims to identify biomarkers and strata that improve personalised treatments for JIA/JIA-uveitis. By bringing together knowledge and data, CLUSTER can conduct novel analyses in this rare, heterogeneous disease. Data harmonisation across existing JIA cohorts facilitates new, larger datasets that would otherwise take years to collect; however, challenges exist as datasets are often collected autonomously. Here we present progress towards a large-scale, unique JIA data resource, bringing together treatment data from 4 real-world JIA treatment studies.Description/MethodFour studies (CAPS, CHARMS, BCRD and BSPAR-ETN; the latter two being part of the UK JIA Biologics register) contributed data into CLUSTER.We created two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi). Variables were selected based on a previously developed core dataset, accounting for different levels of granularity across studies. The same inclusion and exclusion criteria were agreed for both datasets, designed to allow for combined analysis of these.OpenPseudonymiser software encrypted NHS numbers - these were matched cross-study to identify duplicates and checked against known duplicate lists. Errors in NHS numbers and existing duplicate matches were identified and corrected. Each NHS number was assigned a CLUSTER ID, meaning 1 child has the same ID across all relevant studies such that children contributing similar data across multiple studies could be identified.Discussion/ResultsA total of 7013 records (from 5435 individuals) were identified; of which 2882 (41%, corresponding to 1304 individuals) represented the same child across >1 study. 197 individuals had duplicate records within 1 study, 961 in 2 studies, 142 in 3, and 4 children had duplicate records in all 4 studies.After removing 350 MTX and 605 TNFi duplicate entries, the final datasets contain 2899 and 2401 unique MTX and TNFi patients respectively; 1018 are in both datasets having received both treatments. Missingness across core outcome variables ranged from 10% (active joint count MTX timepoint 2) to 60% (physician VAS TNFi timepoint 2) and was not improved through combining datasets with duplicate entries. Specificity in some variables was lost to allow integration by combining data using least common denominators (e.g. ethnicity captured as Caucasian/Non-Caucasian, despite more specific categories available in some studies). Key learning points/ConclusionCombining data across studies has achieved dataset sizes rarely seen in JIA, which is invaluable to progressing research into personalised treatments and disease outcomes. However, losing specificity in some variables and missingness (a known challenge in observational data) and their impact on future analyses requires further consideration. Ongoing work includes identifying patients with both clinical and biological data that can be combined for more in-depth analyses. Both datasets are available for researchers to use via the CLUSTER Consortium Data Management Committee.

Successful stopping of biologic therapy for remission in children and young people with juvenile idiopathic arthritis.

Clinicians concerned about long-term safety of biologics in JIA may consider tapering or stopping treatment once remission is achieved despite uncertainty in maintaining drug-free remission. This analysis aims to (i) calculate how many patients with JIA stop biologics for remission, (ii) calculate how many later re-start therapy and after how long, and (iii) identify factors associated with re-starting biologics. Patients starting biologics between 1 January 2010 and 7 September 2021 in the UK JIA Biologics Register were included. Patients stopping biologics for physician-reported remission, those re-starting biologics and factors associated with re-starting, were identified. Multiple imputation accounted for missing data. Of 1451 patients with median follow-up of 2.7 years (IQR 1.4, 4.0), 269 (19%) stopped biologics for remission after a median of 2.2 years (IQR 1.7, 3.0). Of those with follow-up data (N = 220), 118 (54%) later re-started therapy after a median of 4.7 months, with 84% re-starting the same biologic. Patients on any-line tocilizumab (prior to stopping) were less likely to re-start biologics (vs etanercept; odds ratio [OR] 0.3; 95% CI: 0.2, 0.7), while those with a longer disease duration prior to biologics (OR 1.1 per year increase; 95% CI: 1.0, 1.2) or prior uveitis were more likely to re-start biologics (OR 2.5; 95% CI: 1.3, 4.9). This analysis identified factors associated with successful cessation of biologics for remission in JIA as absence of uveitis, prior treatment with tocilizumab and starting biologics earlier in the disease course. Further research is needed to guide clinical recommendations.

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases

ObjectivesThis study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. MethodsData from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. ResultsWithin the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. ConclusionsBespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

Bridging disconnected networks of first and second lines of biologic therapies in rheumatoid arthritis with registry data: bayesian evidence synthesis with target trial emulation

ObjectivesWe aim to use real-world data in evidence synthesis to optimize an evidence base for the effectiveness of biologic therapies in rheumatoid arthritis to allow for evidence on first-line therapies to inform second-line effectiveness estimates. Study Design and SettingWe use data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis to supplement randomized controlled trials evidence obtained from the literature, by emulating target trials of treatment sequences to estimate treatment effects in each line of therapy. Treatment effects estimates from the target trials inform a bivariate network meta-analysis (NMA) of first-line and second-line treatments. ResultsSummary data were obtained from 21 trials of biologic therapies including two for second-line treatment and results from six emulated target trials of both treatment lines. Bivariate NMA resulted in a decrease in uncertainty around the effectiveness estimates of the second-line therapies, when compared to the results of univariate NMA, and allowed for predictions of treatment effects not evaluated in second-line randomized controlled trials. ConclusionBivariate NMA provides effectiveness estimates for all treatments in first and second line, including predicted effects in second line where these estimates did not exist in the data. This novel methodology may have further applications; for example, for bridging networks of trials in children and adults.

Belimumab for Treating Active Autoantibody-Positive Systemic Lupus Erythematosus: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG’s critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee.This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of ‘high disease activity’. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen.The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company’s updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company’s approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of £12,335 per quality-adjusted life-year (QALY) gained and £30,278 per QALY gained in the company’s and ERG’s base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in £8480 per QALY gained and £29,313 per QALY gained in the company’s and ERG’s base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup.

Associations between psoriatic arthritis and mental health among patients with psoriasis: A replication and extension study using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

Despite some evidence that psoriatic arthritis (PsA) may increase psychological burden in psoriasis, the mental health of this subpopulation is under-investigated. To investigate whether PsA is associated with higher depression and anxiety in moderate-to-severe psoriasis; explore whether pain mediates these associations; and estimate the prevalence of undiagnosed and untreated depression. Baseline data from British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) participants completing the Hospital Anxiety and Depression Scale (HADS) were analysed. 707 patients (n=540 with psoriasis only; n=167 with PsA) were included. Depression prevalence was higher in patients with than without PsA, when a HADS-depression subscale cut-off ≥8 was used (33% vs. 23%, adjusted Odds Ratio [OR] (95% Confidence Intervals [CI])=1.64 (1.09-2.45)), but did not differ using the HADS cut-off≥11. Anxiety prevalence was higher among PsA patients, regardless of HADS cut-off (cut-off≥11: adjusted OR (95% CI)=1.62 (1.07-2.45)). Pain fully mediated the effect of PsA on depression and anxiety in psoriasis. 53.6% of participants identified as depressed did not have a known psychiatric disorder; two thirds of depressed participants were not treated. PsA comorbidity in psoriasis is associated with higher anxiety; its association with depression appears to be robust when milder depressive syndromes are included, but less consistent for higher-threshold depression definitions. Depression remains unrecognized and untreated in over half of moderately-to-severe psoriasis patients. Routine depression and anxiety screening is recommended in psoriasis and PsA. PsA comorbidity may increase depression and anxiety in psoriasis through pain experience.

Drug Survival Associated With Effectiveness and Safety of Treatment With Guselkumab, Ixekizumab, Secukinumab, Ustekinumab, and Adalimumab in Patients With Psoriasis

Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic differently (effect modifiers) may inform the decision to choose between biologics. To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival. We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021. Adalimumab, ustekinumab, secukinumab, guselkumab, ixekizumab. We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety. A total of 16 122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab. The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.

O03: Effect modification of biologic survival by patient characteristics: a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register

O03: Effect modification of biologic survival by patient characteristics: a prospective cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register

P84: Secukinumab treatment results in sustained drug survival in biologic‐naïve and biologic‐experienced patients with moderate‐to‐severe plaque psoriasis: analysis of 24 months of follow‐up data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR)

P84: Secukinumab treatment results in sustained drug survival in biologic‐naïve and biologic‐experienced patients with moderate‐to‐severe plaque psoriasis: analysis of 24 months of follow‐up data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR)

P78: Secukinumab treatment results in sustained improvement in absolute Psoriasis Area and Severity Index and Dermatological Life Quality Index in biologic‐naïve and biologic‐experienced patients with moderate‐to‐severe plaque psoriasis: analysis of 12 months of follow‐up data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR)

P78: Secukinumab treatment results in sustained improvement in absolute Psoriasis Area and Severity Index and Dermatological Life Quality Index in biologic‐naïve and biologic‐experienced patients with moderate‐to‐severe plaque psoriasis: analysis of 12 months of follow‐up data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR)

P93: Demographics and drug survival in patients with psoriasis treated with brodalumab enrolled in the British Association of Dermatologists Biologic and Immunomodulators Interventions Register (BADBIR): an updated analysis up to 18 months

P93: Demographics and drug survival in patients with psoriasis treated with brodalumab enrolled in the British Association of Dermatologists Biologic and Immunomodulators Interventions Register (BADBIR): an updated analysis up to 18 months

Efficacy of Abatacept Versus Tumor Necrosis Factor Inhibitors in Anti-citrullinated Protein Antibody-Positive Patients with Rheumatoid Arthritis: Results from a Korean Nationwide Biologics Registry.

Introduction To compare the efficacy of abatacept and tumor necrosis factor inhibitor (TNFi) in patients with anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) and identify those who benefit most from abatacept over TNFi.MethodsThis observational study identified RA patients who were ACPA-positive and initiated abatacept or TNFi from the Korean College of Rheumatology Biologics and Targeted therapy registry. Propensity score (PS) matching was performed to balance baseline confounding in abatacept- or TNFi-treated patients. The major endpoints were changes in Clinical Disease Activity Index (CDAI) and achievement of CDAI remission/low disease activity after 1 year of treatment. Subgroup analysis was mainly performed stratified by prior biologics use.ResultsA total of 291 PS-matched, ACPA-positive RA patients who initiated abatacept (n = 97) and TNFi (n = 194) were included. From baseline CDAI scores of 26.52 in the abatacept group and 26.38 in the TNFi group, the mean changes after 1 year were − 16.78 and − 13.61, respectively (difference − 3.17, p = 0.020). The proportion of patients achieving CDAI remission/low disease activity was 68.0% with abatacept and 52.6% with TNFi (p = 0.013). In the subgroup analysis, patients that were biologics-naïve had better improvement in CDAI after treatment with abatacept than TNFi (difference − 3.35, p = 0.021).ConclusionsThis real-world study suggests that abatacept may have better clinical response compared to TNFi in patients with established ACPA-positive RA, especially in those that were biologics-naïve.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00467-4.

025 Baseline data from OPTIMISE: MS – a prospective, real word pharmacovigilance study in MS

BackgroundTherapeutic options in MS have increased rapidly, but real-world safety data is limited. Safety signals have emerged from clinical trials and early clinical experience with newer MS therapies, however the rates at which these occur in a real-world, UK MS population is unknown.MethodsOPTIMISE: MS is a longitudinal observational study that will recruit at least 4000 people with MS eligible for DMT from centres across the UK. It will follow them up for at least 5 years in the first instance using electronic case records. Serious adverse events (SAEs), DMT use and disease outcomes will be captured. The study design has been informed by rheumatological biologic registries and is anticipated to expand in scope, as participants consent to be re-contacted regarding sub-studies.ResultsSince its initiation in June 2019, 906 people with MS have enrolled. 72% are female (mean age44.5 (SD 11.1); mean disease duration 8.9 years (SD 7.3)) 95% study population have RRMS and 35% were receiving DMT prior to consent. Data from a larger cohort will be presented.ConclusionsThis study has the potential to deliver clinically meaningful data on the association of MS DMT with serious adverse events in a real-world population. The association of SAEs with lymphopaenia, and prior DMT/DMT switching will be studied. Rates of malignancies will be examined with particular reference to immunosuppressive therapies.ruth.dobson@qmul.ac.uk

AB0416 CARDIOVASCULAR EVENT, VENOUS THROMBOEMBOLIZM, AND INFECTION RISK WITH TOFACITINIB IN RHEUMATOID ARTHRITIS PATIENTS AGED ≥ 60 YEARS

BackgroundTofacitinib is a targeted synthetic DMARD that selectively inhibits Janus kinase (JAK) and is approved for the treatment of RA by the FDA in 2012. In recent years, an important safety concern related to incidence of adverse events after treatment with tofacitinib has emerged.ObjectivesTo evaluate the risk of major adverse cardiovascular events (MACE), venous thromboembolism (pulmonary embolism or deep vein thrombosis), serious infections requiring hospitalization, and herpes zoster with tofacitinib in RA patients aged ≥ 60 years.MethodsHUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single center biological and targeted synthetic DMARD registry since 2005. We analyzed RA patients aged ≥ 60 years receiving tofacitinib who had at least 1 control visit registered in the HURBIO database. Phone calls were made with these patients for the current health status information until the end of January 2022. The data of the patients who lost the follow-up in our clinic were obtained from the personal health record system of the Republic of Turkey Ministry of Health by patients’ permission. The coprimary end points were adjudicated MACE, VTE, serious infections, and herpes zoster. These events were identified using patients’ medical records. Crude incidence rates were expressed in patients with first events per 100 patient-years, with two-sided 95% confidence intervals.ResultsA total of 132 RA patients (109, 82.6% female) aged ≥ 60 years received tofacitinib at a dose of 5 mg twice daily. The median (25–75% percentiles) age was 67 (63-73) years and median duration under tofacitinib was 18 (5-33) months. Approximately 70% of patients were biologically naive. During a median follow-up of 1.5 years, the incidences of serious infection requiring hospitalization and herpes zoster were higher (5.5% [95%CI 3.12-9.86] and 3.4% [1.67-7.17], respectively) while there was no increase in the incidences of MACE and VTE. The causes for hospitalization were as follows: COVID-19 (n=4), pneumonia (n=3), soft-tissue infection (n=3), and GIS infection (n=1). Two of these patients deceased.ConclusionOlder patients with RA are at increased infection risk because of age and comorbid conditions. Although adverse events are reported with 10 mg tofacitinib twice daily, clinicians should be careful against the risk of infection at a dose of 5 mg twice daily, especially in elderly patients.

OA09 Gene expression analysis reveals distinct ancestry-specific profiles associated with response to rituximab in SLE

Abstract Background/Aims SLE patients of European ancestry frequently have milder and more treatment-responsive disease which is poorly explained. Transcriptional signatures are one approach to stratifying SLE which can distinguish by disease activity, autoantibodies and organ involvement but also vary significantly between patients of different ancestry. We developed two interferon-stimulated gene expression scores (IFN-Score-A and IFN-Score-B) that predict clinical outcomes in SLE. Additional modules of differentially expressed genes associated with disease activity have been described but have not been evaluated for association with ancestry or treatment response. Here, we evaluated the association between pre-defined transcriptional scores for these previously described modules, ancestry and response to B cell depletion with rituximab in a multi-ethnic UK cohort with active SLE. Methods Baseline gene expression was evaluated in pre-treatment whole blood using a customised 96-probe Taqman array in 213 patients with active SLE prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Register on commencing biologic therapy. Interferon status was evaluated using IFN-Score-A and IFN-Score-B as previously described. Gene expression scores representing Plasmablast, Neutrophil, Myeloid and Inflammation-annotated modules were represented by the median expression of 4-16 genes per annotation. Response to first cycle rituximab was evaluable in 110 patients and was defined by BILAG-2004 criteria at 6 months. Results 128 patients were of European ancestry and 85 were of African ancestry, Subcontinental Asian, East Asian or mixed race. Transcriptional signatures differed between ancestral groups. Patients of European ancestry had lower baseline IFN-scores than non-European ancestries. IFN-scores among European patients were highly correlated with Plasmablast (R2=0.32), Neutrophil (R2=0.54), Myeloid (R2=0.72) and Inflammation (R2=0.62) -annotated scores (p < 0.001). Among patients of non-European ancestry the picture was more heterogeneous; IFN-scores showed no correlation with Neutrophil (R2=0.19, p = 0.08) or Plasmablast (R2=0.02, p = 0.83) scores and their correlation with the other annotations was weaker. Overall BILAG response to rituximab was observed in 70/110 (63%) patients. However, transcript-level hierarchical clustering in non-European ancestry patients revealed distinct profiles for response to rituximab. Cluster 1 were IFN-low and were older with lower serological activity and higher glucocorticoid use. Response to rituximab was observed in only 14%. Cluster 2 were IFN-high with low Neutrophil, Myeloid and Inflammation signatures. 42% achieved a BILAG response to rituximab. Cluster 3 showed globally high expression across all transcript annotations and best response rate to rituximab at 84%. Clusters 2 and 3 were clinically and serologically similar. Clusters derived from European ancestry patients were not significantly associated with response to rituximab but were distinguished by renal involvement. Conclusion We describe distinct transcriptional profiles in a multi-ethnic UK SLE cohort. Baseline gene expression, in particular IFN status, stratified response to rituximab among non-European subjects but was not prognostic among European patients. Development of transcriptional biomarkers should account for ancestral variation. Disclosure L. Carter: None. A. Alase: None. Z. Wigston: None. A. Psarras: None. A. Burska: None. M. Md Yusof: Consultancies; YY has provided consultancy to UCB. J.A. Reynolds: None. M. Wittmann: Consultancies; MW has received consultancy fees from Abbvie, Celgene, Janssen, L’Oreal, Novartis and Pfizer. I. Bruce: Consultancies; IB has provided consultancy to AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono. Grants/research support; IB has received research funding from Genzyme Sanofi & GlaxoSmithKline. E.M. Vital: Consultancies; MEV has provided Consultancies to Genentech, AstraZeneca, Aurinia, Lilly and Modus Therapeutics. Grants/research support; EMV has received research funding from Astra Zeneca and Sandoz.

OA17 The risk of inflammatory bowel disease in patients with axial spondyloarthritis treated with biologic agents: data from the BSR registry in axial spondyloarthritis (BSRBR-AS) and meta-analysis

Abstract Background/Aims Inflammatory bowel disease (IBD) is one of the extra-musculoskeletal manifestations associated with axial spondyloarthritis (axSpA). A previous meta-analysis reported a pooled prevalence of 6.8% (95% CI 6.1% to 7.7%). Amongst those commencing anti-TNFα therapy in BSRBR-AS it has been reported that patients with IBD were much less likely to have been prescribed etanercept (a soluble fusion protein) in comparison to the monoclonal antibodies in this cohort (adalimumab, certolizumab pegol and golimumab). A large study from Denmark of approximately 80,000 patients with an autoimmune disease (other than IBD) for which anti-TNFα therapy is an indication found a significant excess risk of IBD in those treated with etanercept, an excess which was not observed with other anti-TNFα agents. We therefore aimed to determine, amongst patients in BSRBR-AS, whether the risk of inflammatory bowel disease (IBD) varies between patients treated with biologic and other therapies, and whether specifically the risk is higher in patients treated with etanercept. Methods The British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) was used to determine the incidence of IBD during follow-up and to calculate the incidence rate difference (IRD) between biologic treatment and other treatment groups. We thereafter conducted a systematic review (involving observational studies and randomised controlled trials) to perform a meta-analysis to quantify the difference in incidence of IBD between treatment groups. Results In BSRBR-AS, among people with axSpA, exposure to biologic therapy was associated with an increased incidence of IBD compared to non-exposed patients (IRD 12.4 95% CI [5.5-19.4]). In meta-analysis, this finding was replicated across observational studies but not seen in placebo controlled RCTs IRD 2.2 95% CI (-4.1-8.5). Data from BSRBR-AS do not suggest that excess incidence of IBD is associated with exposure to etanercept compared to other anti-TNFα therapies (IRD -1.9 per 1000 py 95% CI [-15.2-11.5]). Trials and their extensions suggest a small (and not statistically significant) absolute increased incidence associated with etanercept of between 2.1 and 5.6 per 1000py compared to other anti-TNFα therapies. Conclusion An excess risk of IBD amongst persons treated with biologics is likely not causal but evidence from trials suggest that etanercept is associated with an increased risk compared to other anti-TNFα therapies, albeit with considerable uncertainty. Disclosure G.J. Macfarlane: Grants/research support; GJM is Chief Investigator a grant from BSR to fund the AS register. BSR received funds from Pfizer, AbbVie and UCB to support this work. R. Biallas: None. L.E. Dean: None. G.T. Jones: Grants/research support; GTJ is Co-Investigator on a grant from BSR to fund the AS register. BSR received funds from Pfizer, AbbVie and UCB to support this work. N. Goodson: Other; NG is Chair of the BSR Registers Committee. O. Rotariu: None.

OA19 Successes and challenges in harmonising four national juvenile idiopathic arthritis cohorts: an example from CLUSTER consortium

Abstract Background/Aims The CLUSTER consortium aims to identify biomarkers and strata that improve personalised treatments for JIA/JIA-uveitis. By bringing together knowledge and data, CLUSTER can conduct novel analyses in this rare, heterogeneous disease. Data harmonisation across existing JIA cohorts facilitates new, larger datasets that would otherwise take years to collect; however, challenges exist as datasets are often collected autonomously. Here we present progress towards a large-scale, unique JIA data resource, bringing together treatment data from four real-world JIA treatment studies. Methods Four studies (CAPS, CHARMS, BCRD and BSPAR-ETN; the latter two being part of the UK JIA Biologics register) contributed data into CLUSTER. We created two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi). Variables were selected based on a previously developed core dataset, accounting for different levels of granularity across studies. The same inclusion and exclusion criteria were agreed for both datasets, designed to allow for combined analysis of these. OpenPseudonymiser software encrypted NHS numbers - these were matched cross-study to identify duplicates and checked against known duplicate lists. Errors in NHS numbers and existing duplicate matches were identified and corrected. Each NHS number was assigned a CLUSTER ID, meaning one child has the same ID across all relevant studies such that children contributing similar data across multiple studies could be identified. Results A total of 7013 records (from 5435 individuals) were identified, of which 2882 (41%, corresponding to 1304 individuals) represented the same child across >1 study. 197 individuals had duplicate records within one study, 961 in two studies, 142 in three, and four children had duplicate records in all four studies. After removing 350 MTX and 605 TNFi duplicate entries, the final datasets contain 2899 and 2401 unique MTX and TNFi patients respectively; 1018 are in both datasets having received both treatments. Missingness across core outcome variables ranged from 10% (active joint count MTX timepoint 2) to 60% (physician VAS TNFi timepoint 2) and was not improved through combining datasets with duplicate entries. Specificity in some variables was lost to allow integration by combining data using least common denominators (e.g. ethnicity captured as Caucasian/Non-Caucasian, despite more specific categories available in some studies). Conclusion Combining data across studies has achieved dataset sizes rarely seen in JIA, which is invaluable to progressing research into personalised treatments and disease outcomes. However, losing specificity in some variables and missingness (a known challenge in observational data) and their impact on future analyses requires further consideration. Ongoing work includes identifying patients with both clinical and biological data that can be combined for more in-depth analyses. Both datasets are available for researchers to use via the CLUSTER Consortium Data Management Committee. Disclosure S. Lawson-Tovey: None. L.R. Wedderburn: Consultancies; L.W. reports consulting fees from Pfizer unrelated to this work. Grants/research support; CLUSTER consortium receives support from AbbVie, UCB, Pfizer, Sobi and GSK. N. Geifman: None. M. Barnes: None. K.L. Hyrich: Grants/research support; KLH reports grant income from BMS, UCB, and Pfizer. Other; KLH reports non-personal speaker's fees from Abbvie.

OA14b Etanercept originator versus its biosimilar (SB4) for the treatment of rheumatoid arthritis. Are they truly similar?

Abstract Background/Aims Etanercept biosimilar SB4 (ETN-B) showed comparable efficacy to its biologic originator (ETN-O) among biologic-naïve patients with rheumatoid arthritis (RA) in randomised controlled trials. Subsequently, a nationwide guideline in the United Kingdom (UK) obligated the prescription of biosimilars in 2016, resulting in significant cost-savings to the NHS. However, real-world evidence comparing ETN-O and ETN-B is limited. This analysis aims to compare the effectiveness of ETN-O versus ETN-B amongst biologic-naïve patients with RA treated in routine clinical practice in the UK. Methods The British Society for Rheumatology Biologics Register for RA (BSRBR-RA) is a prospective observational cohort study. This analysis included patients starting their first biologic (ETN-O or ETN-B), recruited since 2010, with at least one follow-up. Baseline data are collected at start of therapy, including patient demographics and disease activity. Follow-up data are collected six monthly for the first three years and annually thereafter, including changes in disease activity and anti-rheumatic therapy. Key outcomes assessed were change in Disease Activity Score for 28-joints (DAS28), DAS28 remission, EULAR treatment response, change in Health Assessment Questionnaire (HAQ), and minimal clinically important difference (MCID) in HAQ. Drug retention was explored using Kaplan-Meier and Cox-regression analyses, along with reasons for treatment withdrawal. Multiple imputation was used to account for missing data and confounding by indication was accounted for using propensity-decile adjustment. Results This analysis included 1927 patients with RA starting their first biologic therapy: 996 (52%) ETN-O and 931 (48%) ETN-B. At six-months, change in DAS28 and HAQ were similar between therapies (Table). There were no differences in key imputed propensity adjusted outcomes (odds ratio [95% confidence interval]): DAS28 remission: 0.90 (0.7-1.1, p = 0.3); MCID in HAQ: 0.86 (0.7-1.1, p = 0.3) and EULAR treatment response: 0.96 (0.8-1.2, p = 0.8). One-year retention rates were 69% (95% CI: 66-72) for ETN-O and 70% (95% CI: 67-73) for ETN-B and the main reasons for treatment withdrawal were adverse events and ineffectiveness for both drugs. Conclusion This analysis is the first to our knowledge to show similar outcomes amongst biologic-naïve patients with RA treated with either ETN-O or ETN-B using real-world data, which brings further evidence for similarity between the drugs. Disclosure A. Rokad: None. L. Kearsley-Fleet: None. K. Watson: None. M. Lunt: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; Pfizer, BMS.

OA14a Outcomes after switching from etanercept originator to its biosimilar (SB4) for the treatment of rheumatoid arthritis

Abstract Background/Aims Following the etanercept biosimilar SB4 (ETN-B) launch in the UK in 2016, nationwide guidelines encourage patients switch from the biologic originator (ETN-O) to ETN-B, known as non-medical switching (NMS). However, the long-term implications of NMS have not yet been analysed nationally among patients with rheumatoid arthritis (RA). This analysis aims to evaluate treatment outcomes and drug retention after patients with RA are switched from ETN-O to ETN-B in routine clinical practice in the UK. Methods The British Society for Rheumatology Biologics Register for RA (BSRBR-RA) is a prospective observational cohort study. This analysis included all patients who switched from ETN-O to ETN-B since 2016. Disease activity was assessed at the time of switch and after six months. Key outcomes included change in disease activity (DAS28), DAS28 remission and EULAR treatment response. Drug retention was analysed using Kaplan-Meier and treatment withdrawal reasons were explored for all patients who switched to ETN-B, as well as (1) patients who switched-back to ETN-O, (2) patients who changed to a non-ETN biologic, (3) patients discontinuing all biologic therapy. Multiple imputation was used to account for missing data. Results 1160 patients with RA switched from ETN-O to ETN-B. Of the 919 (79%) with available DAS28 data, there was no change in six-month DAS28 score following switch (median: 0, IQR: -0.8, 0.7). After a median follow-up of 1.8 years (IQR: 1.0, 2.3), most patients remained on ETN-B (N = 844, 73%) with the main treatment withdrawal reason being ineffectiveness (N = 139, 44%). Among those who discontinued ETN-B, 133 (11%) patients switched-back to ETN-O and 98 (8%) patients changed to a non-ETN biologic; both primarily due to ineffectiveness (Table). Lastly, 85 (7%) patients discontinued all biologic therapy mainly due to adverse events (N = 50, 59%). Conclusion This analysis has demonstrated sustained effectiveness after switching from ETN-O to ETN-B using real-world nationwide data. Among the sub-cohorts of patients who discontinued ETN-B, differences were observed regarding the frequency and reasons for treatment withdrawal. These results will support UK rheumatologists and patients with treatment decisions, assist quality improvement projects to reduce drug withdrawals and refine biologic treatment delivery in the UK. Disclosure A. Rokad: None. L. Kearsley-Fleet: None. K. Watson: None. M. Lunt: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; Pfizer, BMS.

Celebrating 33years of the DRFZ: Epidemiology and Health Services Research

Der wissenschaftliche Fokus des Programmbereichs Epidemiologie und Versorgungsforschung des DRFZ liegt einerseits auf der Erforschung der Versorgungssituation rheumakranker Menschen in Deutschland einschließlich ihrer Defizite, Fortschritte und zeitlichen Trends. Andererseits ist ein wesentliches Ziel, durch die langfristige Beobachtung von Krankheitsverläufen in großen Kohorten Risikofaktoren für ungünstige Krankheitsverläufe, aber auch protektive Faktoren aufzudecken. Mit der Zulassung innovativer, zielgerichteter Therapien zu Beginn dieses Jahrtausends wurde die Thematik der Sicherheit und Wirksamkeit der verschiedenen antirheumatischen Therapien unter Alltagsbedingungen zu einer für Ärzte und Patienten vorrangigen Frage. Die Biologika-Register entwickelten sich zu zentralen Instrumenten des Programmbereichs, mit denen Fragen zur vergleichenden Therapiesicherheit, aber auch zur Therapiewirksamkeit und Reduktion von Risiken durch wirksame Therapie, belastbar beantwortet werden können.Im vorliegenden Artikel werden ausgewählte Ergebnisse epidemiologischer Forschung am DRFZ dargestellt. Das übergreifende Ziel der Forschung war und ist es, zur Verbesserung der Lebensqualität rheumakranker Kinder und Erwachsener beizutragen. Dem dient die klinisch-evaluative Versorgungsforschung ebenso wie die Gewinnung von Erkenntnissen, die eine wirksame, individualisierte Therapie unterstützen. Als unverzichtbare Instrumente haben sich große, langfristige Patientenkohorten und ein stabiles Netzwerk mit den klinisch tätigen Rheumatologen und Betroffenen erwiesen.