Comparative effectiveness of a second TNF inhibitor versus a non-TNF biologic in the treatment of polyarticular course juvenile idiopathic arthritis.

OBJECTIVE: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non-TNFi biologic following discontinuation of a TNFi for patients with polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, patients with pJIA who started a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on index date and a visit 6 months after the index date. Outcome measures included clinical juvenile arthritis disease activity score 10 (cJADAS10), cJADAS10 inactive disease (ID<2.5) and cJADAS10 minimal disease activity (MiDA<5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aOR) were calculated using propensity score quintiles to compare outcomes at 6 months following second biologic initiation. RESULTS: There were 216 patients included, 84% initially received etanercept and most patients stopped it for ineffectiveness (74%). 183 (85%) started a second TNFi and 33 (15%) started a non-TNFi. Adalimumab was the most common second biologic (71% overall, 84% of second TNFi) and tocilizumab was the most common non-TNFi second biologic (9% overall, 58% of non-TNFi). There was no difference between TNFi and non-TNFi in cJADAS ID (29% versus 25%; aOR 1.23 [0.47-3.20]) or at least MiDA (43% versus 39%; aOR 1.11 [0.47-2.62]) at 6 months. CONCLUSION: Most patients with polyarticular course JIA started TNFi rather than non-TNFi as their second biologic, and there were no differences in disease activity at 6 months.

Barriers and enablers to engagement in exercise and physical activity in non-English speaking South Asian people with chronic musculoskeletal disease.

BACKGROUND: Exercise and physical activity (EPA) are recommended for people with chronic musculoskeletal disease; however, lower levels of engagement with EPA has been consistently reported in people from the South Asian community across a range of diseases. As language can pose a significant barrier in healthcare, this study aimed to understand the enablers and barriers to the acceptance of EPA among non-English speaking South Asian people who attended rheumatology clinics. METHODS: 12 non-English speaking individuals from the South Asian community who had chronic musculoskeletal disease with significant pain scores were interviewed via telephone or face-to-face in their spoken languages. The audio recordings of the interviews were translated into English and transcribed verbatim. Data was analysed using thematic analysis implemented in the NVivo 12 Pro software program. RESULTS: The mean age was 52 years (9 women and 2 men). One main theme was identified: 'Enablers and barriers to exercise and physical activity'. Enablers to EPA were having knowledge about the benefits of EPA, being given resources in a language that they understood, and supportive environments such as having access to community facilities for those who could not undertake EPA in their houses. Barriers included physical health such as pain and fatigue, lack of time, difficulties with transportation to exercise venues, dislike of group exercises and lack of understanding of what and how to do exercise and be physically active. Participants' beliefs about EPA and whether they impacted their physical health seemed to influence whether they were undertaken or not. There was a perception that their culture shaped their compatriots' beliefs about EPA, and it was not normal practice for people from their country of birth to engage in it. CONCLUSIONS: This is the first qualitative study to explore the barriers and enablers to engagement in EPA in non-English speaking South Asian people with chronic musculoskeletal disease. Modifiable factors such as addressing the level of knowledge on the benefits of EPA in the management of chronic joint and muscle pain; aiding the development of the skills required to exercise safely and confidently despite chronic pain and providing information and services in the native language could promote the EPA engagement of non-English speaking South Asian individuals with chronic musculoskeletal disease. The findings may inform improvements within clinical services to promote the benefits, impact and self-efficacy of engagement with EPA as part of chronic musculoskeletal disease management. ETHICS APPROVAL: The West Midlands-Edgbaston Research Ethics Committee (reference:20/WM/0305).

Annals of the Rheumatic Diseases collection on pregnancy 2018-2023: observational data-driven knowledge.

Pregnancy can be an exciting time but for those living with rheumatic musculoskeletal diseases (RMDs), it can also be a time fraught with concern, including what effect pregnancy will have on the underlying RMD and what effect the RMD may have on the pregnancy and the baby, including the effects of medications. Generating an evidence base in pregnancy is challenging. Few interventional trials of medications in RMD pregnancies have ever been conducted, often for concerns of safety for both the mother and the child. Therefore, observational research remains important for informing clinical practice and helping women with RMDs make decisions regarding their health preconception and during pregnancy. The Annals of the Rheumatic Diseases (ARD) continues to publish important research on pregnancy in RMDs to increase the evidence base on this subject. Here we present an overview of papers published on this topic between January 2018 and December 2023. Our focus includes papers on pregnancy and RMD outcome, the effects of drug exposure, fetal outcomes as well as fertility.

Towards stratified treatment of JIA: machine learning identifies subtypes in response to methotrexate from four UK cohorts.

BACKGROUND: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. METHODS: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year. Clusters of MTX 'response' were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. FINDINGS: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65-0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. INTERPRETATION: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA. FUNDING: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and the National Institute for Health Research.

Overlap of International League of Associations for Rheumatology and Preliminary Pediatric Rheumatology International Trials Organization Classification Criteria for Nonsystemic Juvenile Idiopathic Arthritis in an Established UK Multicentre Inception Cohort.

OBJECTIVE: The goal was to assess the degree of overlap between existing International League of Associations for Rheumatology (ILAR) and preliminary Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria for juvenile idiopathic arthritis (JIA). METHODS: Participants from the Childhood Arthritis Prospective Study, a multicenter UK JIA inception cohort, were classified using the PRINTO and ILAR classification criteria into distinct categories. Systemic JIA was excluded because several classification items were not collected in this cohort. Adaptations to PRINTO criteria were required to apply to a UK health care setting, including limiting the number of blood biomarker tests required. The overlap between categories under the two systems was determined, and any differences in characteristics between groups were described. RESULTS: A total of 1,223 children and young people with a physician's diagnosis of JIA were included. Using PRINTO criteria, the majority of the patients had "other JIA" (69.5%). There was a high degree of overlap (91%) between the PRINTO enthesitis/spondylitis- and ILAR enthesitis-related JIA categories. The PRINTO rheumatoid factor (RF)-positive category was composed of 48% ILAR RF-positive polyarthritis and 52% undifferentiated JIA. The early-onset antinuclear antibodies-positive PRINTO category was largely composed of ILAR oligoarthritis (50%), RF-negative polyarthritis (24%), and undifferentiated JIA (23%). A few patients were unclassified under PRINTO (n = 3) and would previously have been classified as enthesitis-related JIA (n = 1) and undifferentiated JIA (n = 2) under ILAR. CONCLUSION: Under the preliminary PRINTO classification criteria for childhood arthritis, most children are not yet classified into a named category. These data can help support further delineation of the PRINTO criteria to ensure homogenous groups of children can be identified.

Therapeutic advances in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common immune mediated inflammatory diseases. People with rheumatoid arthritis present with pain, swelling, and stiffness that typically affects symmetrically distributed small and large joints. Without effective treatment, significant joint damage, disability, and work loss develop, owing to chronic inflammation of the joint lining (synovium). Over the past 25 years, the management of this condition has been revolutionized, resulting in substantially higher levels of disease remission and better long term outcomes. This improvement reflects a paradigm shift towards early and aggressive pharmacological intervention coupled with a proliferation in treatment choice, in turn related to enhanced pathobiological understanding and the advent of new drugs for rheumatoid arthritis. Following an overview of these developments from a historical perspective, and with a general audience in mind, this review focuses on newer, targeted treatments in an ever evolving landscape. The review highlights ongoing areas of debate and unmet need, including the proportion of patients with persistent, difficult-to-treat disease, despite recent advances. Also discussed are personalized, strategic approaches to individual patients, the role for imaging in clinical decision making, and the goal of sustained, drug free remission and disease prevention in the future.

Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis.

OBJECTIVE: To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment. METHODS: Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorized as 20% most deprived, middle 40% or 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g. smoking, BMI) as potential mediators. RESULTS: 16 085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups, respectively. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36% and 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95% CI 0.22, 0.37) and were less likely to achieve low disease activity (odds ratio [OR] 0.76; 95% CI 0.68, 0.84) in unadjusted models. Results were similar for 3-month DAS28 (ß = 0.23; 95% CI 0.11, 0.36) and low disease activity (OR 0.77; 95% CI 0.63, 0.94). The most deprived were more likely to discontinue treatment (hazard ratio 1.18; 95% CI 1.12, 1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated. CONCLUSION: Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities.

Impact of Risk Factors on COVID-19 Outcomes in Unvaccinated People With Rheumatic Diseases: A Comparative Analysis of Pandemic Epochs Using the COVID-19 Global Rheumatology Alliance Registry.

OBJECTIVE: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern. METHODS: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types. RESULTS: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes. CONCLUSION: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the 'JAK-pot' study).

BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

Developing and externally validating multinomial prediction models for methotrexate treatment outcomes in patients with rheumatoid arthritis: results from an international collaboration.

OBJECTIVES: In rheumatology, there is a clinical need to identify patients at high risk (>50%) of not responding to the first-line therapy methotrexate (MTX) due to lack of disease control or discontinuation due to adverse events (AEs). Despite this need, previous prediction models in this context are at high risk of bias and ignore AEs. Our objectives were to (i) develop a multinomial model for outcomes of low disease activity and discontinuing due to AEs 6 months after starting MTX, (ii) update prognosis 3-month following treatment initiation, and (iii) externally validate these models. STUDY DESIGN AND SETTING: A multinomial model for low disease activity (submodel 1) and discontinuing due to AEs (submodel 2) was developed using data from the UK Rheumatoid Arthritis Medication Study, updated using landmarking analysis, internally validated using bootstrapping, and externally validated in the Norwegian Disease-Modifying Antirheumatic Drug register. Performance was assessed using calibration (calibration-slope and calibration-in-the-large), and discrimination (concordance-statistic and polytomous discriminatory index). RESULTS: The internally validated model showed good calibration in the development setting with a calibration-slope of 1.01 (0.87, 1.14) (submodel 1) and 0.83 (0.30, 1.34) (submodel 2), and moderate discrimination with a c-statistic of 0.72 (0.69, 0.74) and 0.53 (0.48, 0.59), respectively. Predictive performance decreased after external validation (calibration-slope 0.78 (0.64, 0.93) (submodel 1) and 0.86 (0.34, 1.38) (submodel 2)), which may be due to differences in disease-specific characteristics and outcome prevalence. CONCLUSION: We addressed previously identified methodological limitations of prediction models for outcomes of MTX therapy. The multinomial approach predicted outcomes of disease activity more accurately than AEs, which should be addressed in future work to aid implementation into clinical practice.

The incidence and prevalence of Juvenile Idiopathic Arthritis differs between ethnic groups in England.

OBJECTIVES: Juvenile Idiopathic Arthritis (JIA) is a heterogenous group of rare autoimmune disorders characterised by chronic joint inflammation of unknown aetiology with onset under 16years. Accurate estimates of disease rates help understand impacts on individuals and society, and provide evidence for health service planning and delivery. This study aimed to produce the first national estimates of incidence and prevalence by ethnic group using electronic health records. METHODS: Data from the Clinical Practice Research Datalink (CPRD) Aurum, a primary care electronic health record database in England, were used to estimate the incidence and prevalence of JIA by ethnic group amongst children and young people aged under 16 years between 2003 and 2018, with cases validated using Hospital Episode Statistics (HES). Chi square was used to test the difference in proportions compared to the ethnic distribution of England. RESULTS: A total of 424 incident cases of JIA were identified, 389 validated using HES records. Incidence of JIA was higher amongst those of White ethnic group (6.2 per 100,000 population) compared to Mixed (3.0 per 100,000), Asian (2.7 per 100,000) and Black (2.9 per 100,000) communities. The ethnic group distribution of cases differed significantly compared to the general population (p < 0.0001). CONCLUSION: Incidence and prevalence of JIA differs between ethnic groups, and is different from the population. This is likely to be due to a combination of genetic and equity factors. Further research to understand the underlying cause of these differences is important, to enable targeted interventions and appropriate service provision.

The epidemiology of psoriatic arthritis in the UK: a health intelligence analysis of UK Primary Care Electronic Health Records 1991-2020.

OBJECTIVES: Epidemiological estimates of psoriatic arthritis (PsA) underpin the provision of healthcare, research, and the work of government, charities and patient organizations. Methodological problems impacting prior estimates include small sample sizes, incomplete case ascertainment, and representativeness. We developed a statistical modelling strategy to provide contemporary prevalence and incidence estimates of PsA from 1991 to 2020 in the UK. METHODS: Data from Clinical Practice Research Datalink (CPRD) were used to identify cases of PsA between 1st January 1991 and 31st December 2020. To optimize ascertainment, we identified cases of Definite PsA (≥1 Read code for PsA) and Probable PsA (satisfied a bespoke algorithm). Standardized annual rates were calculated using Bayesian multilevel regression with post-stratification to account for systematic differences between CPRD data and the UK population, based on age, sex, socioeconomic status and region of residence. RESULTS: A total of 26293 recorded PsA cases (all definitions) were identified within the study window (77.9% Definite PsA). Between 1991 and 2020 the standardized prevalence of PsA increased twelve-fold from 0.03 to 0.37. The standardized incidence of PsA per 100,000 person years increased from 8.97 in 1991 to 15.08 in 2020, an almost 2-fold increase. Over time, rates were similar between the sexes, and across socioeconomic status. Rates were strongly associated with age, and consistently highest in Northern Ireland. CONCLUSION: The prevalence and incidence of PsA recorded in primary care has increased over the last three decades. The modelling strategy presented can be used to provide contemporary prevalence estimates for musculoskeletal disease using routinely collected primary care data.

Outcomes following switching from etanercept originator to etanercept biosimilar in 1024 RA patients: A matched-analysis of the BSRBR-RA.

OBJECTIVES: Adults with RA are being switched from etanercept originator to biosimilar in non-medical/cost-saving switching. This analysis aims to investigate outcomes in these patients, including (a) drug survival and (b) disease activity at six and 12-month, compared with those who remain on originator. METHODS: Using BSRBR-RA, those who switched directly from etanercept originator to biosimilar were identified and matched to patients receiving originator, based on gender, age, disease duration, originator start year. Drug survival was calculated; Cox-proportional hazard models assessed differences in drug persistence between those who switched versus remaining on originator. Change in DAS28 after six and 12-months was compared between cohorts. Multiple imputation was used. RESULTS: 1024 adults with RA switching from etanercept originator to biosimilar were included, with a matched cohort of patients remaining on originator. Patients who switched onto a biosimilar product were no more likely to discontinue etanercept treatment versus those who remained on originator; hazard ratio 1.06 (95%CI 0.89-1.26), with 65% of patients remaining on treatment at three years. Ninety-five (9%) patients switched back to originator within the first year. After six and 12-months, biosimilar patients were no more likely to have a worsening of DAS28 (>0.6units) compared with those who remained on originator. CONCLUSIONS: This is the largest matched comparative effectiveness analysis showing patients switched from etanercept originator to biosimilar appear to do just as well with regards to disease activity and drug persistence compared with those who remained on originator. These data will be reassuring to clinicians and patients regarding non-medical switching.

Evaluation of serious infections, including Mycobacterium tuberculosis, during treatment with biologic disease-modifying antirheumatic drugs: does line of therapy matter?

OBJECTIVES: This study aimed to evaluate if and how the incidence of serious infection (SI) and active tuberculosis (TB) differ among seven biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) considering the line of therapy. METHODS: Patients with RA from the British Society for Rheumatology Biologics Register-RA cohort who initiated etanercept, certolizumab, infliximab, adalimumab, abatacept, rituximab, or tocilizumab from the first to fifth line of therapy were included. Follow-up extended up to three years. Primary outcome was SI, secondary outcome was TB. Event rates were calculated and compared using Cox proportional-hazards, controlling for confounding with inverse probability of treatment weights. Comparisons were made overall and stratified by line of therapy. Sensitivity analysis restricted to all treatment courses from 2009 (tocilizumab availability) until end of study (2018). RESULTS: Among 33 897 treatment courses (62 513 patient-years) the incidence of SI was 4.4/100 patient-years (95%CI 4.2-4.5). After adjustment, hazards ratios (HR) of SI were slightly higher with adalimumab and infliximab compared with etanercept. However, no clear pattern was observed when stratifying by line of therapy, in terms of incidence rate or hazards ratio. Sensitivity analyses showed similar HR among these treatments. Regarding TB, all 49 cases occurred during the first three lines of treatment and rarely since 2009. CONCLUSION: The risk of serious infections does not appear to be influenced by the line of therapy in patients with RA. However, the risk of tuberculosis seems to be more frequent during the initial lines of treatment or prior to 2009.

The successes and challenges of harmonising juvenile idiopathic arthritis (JIA) datasets to create a large-scale JIA data resource.

BACKGROUND: CLUSTER is a UK consortium focussed on precision medicine research in JIA/JIA-Uveitis. As part of this programme, a large-scale JIA data resource was created by harmonizing and pooling existing real-world studies. Here we present challenges and progress towards creation of this unique large JIA dataset. METHODS: Four real-world studies contributed data; two clinical datasets of JIA patients starting first-line methotrexate (MTX) or tumour necrosis factor inhibitors (TNFi) were created. Variables were selected based on a previously developed core dataset, and encrypted NHS numbers were used to identify children contributing similar data across multiple studies. RESULTS: Of 7013 records (from 5435 individuals), 2882 (1304 individuals) represented the same child across studies. The final datasets contain 2899 (MTX) and 2401 (TNFi) unique patients; 1018 are in both datasets. Missingness ranged from 10 to 60% and was not improved through harmonisation. CONCLUSIONS: Combining data across studies has achieved dataset sizes rarely seen in JIA, invaluable to progressing research. Losing variable specificity and missingness, and their impact on future analyses requires further consideration.

The impact of psoriasis on wellbeing and clinical outcomes in juvenile psoriatic arthritis.

OBJECTIVES: Juvenile psoriatic arthritis (JPsA) has varied clinical features that are distinctive to other juvenile idiopathic arthritis (JIA) categories. This study investigates whether such features impact patient-reported and clinical outcomes. METHODS: Children and young people (CYP) were selected if recruited to the Childhood Arthritis Prospective Study, a UK multicentre JIA inception cohort, between January 2001 and March 2018. At diagnosis, patient/parent-reported outcomes (as age-appropriate) included the parental global assessment (10 cm VAS), functional ability (CHAQ), pain (10 cm VAS), health-related quality of life (CHQ psychosocial score), mood/depressive symptoms (MFQ) and parent psychosocial health (GHQ). Three-year outcome trajectories have previously been defined using active joint counts, physician and parent global assessments (PGA, PaGA respectively). Patient-reported outcomes and outcome trajectories were compared in i) CYP with JPsA versus other JIA categories, ii) CYP within JPsA, with and without psoriasis via multivariable linear regression. RESULTS: There were no significant differences in patient-reported outcomes at diagnosis between CYP with JPsA and non-JPsA. Within JPsA, those with psoriasis had more depressive symptoms (coefficient = 9.8, 95% CI = 0.5-19.0) than those without psoriasis at diagnosis. CYP with JPsA had 2.3 times the odds of persistent high PaGA than other ILAR categories, despite improving joint counts and PGA (95% CI 1.2, 4.6). CONCLUSION: CYP with psoriasis at JPsA diagnosis report worse mood, supporting a greater disease impact in those with both skin and joint involvement. Multidisciplinary care with added focus to support wellbeing in children with JPsA plus psoriasis may help improve these outcomes.

A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures.

OBJECTIVES: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are widely used in patients with rheumatoid arthritis (RA), but response to bDMARDs is heterogeneous. The objective of this work was to identify pre-treatment proteomic biomarkers associated with RA clinical outcome measures in patients starting bDMARDs. METHODS: Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to generate spectral maps of sera from patients with RA before and after three months of treatment with the bDMARD etanercept. Protein levels were regressed against RA clinical outcome measures, namely, Disease Activity Score of 28 Joints (DAS28) and its sub-components and DAS28 < 2.6 (i.e. remission). The proteins with the strongest evidence for association were analysed in an independent, replication dataset. Finally, sub-network analysis was carried out using the DIAMOnD algorithm and biological plausibility of identified proteins was assessed by enrichment analysis. RESULTS: 180 patients with RA were included in the discovery dataset and 58 in the validation dataset from a UK-based prospective multicentre study. Ten individual proteins were found to be significantly associated with RA clinical outcome measures. The association of TCPH with DAS28 remission was replicated in an independent cohort. Sub-network analysis of the ten proteins from the regression analysis identified the ontological theme with the strongest associations being with acute phase and acute inflammatory responses. CONCLUSION: This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response to this drug, one of which replicated in an independent cohort.

Development of a sensitive biochemical assay for the detection of tofacitinib adherence.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Tofacitinib is a Janus Kinase inhibitor licensed for the treatment of RA that, unlike biologic anti-rheumatic drugs, is administered orally, but studies of long-term treatment adherence rates are lacking. The measurement of adherence, however, is challenging and there is currently no gold standard test for adherence. Here, we developed a novel HPLC MS/MS assay for the quantification of tofacitinib. The assay demonstrated a LLOQ for tofacitinib of 0.1 ng ml-1, within run accuracy was 81-85% at LLOQ and 91-107% at all other levels. To investigate the ability of the assay to detect adherence, tofacitinib was measured in a random selection of serum samples (n = 10) of tofacitinib treated RA patients who self-reported adherent behaviour. The assay measured tofacitinib in all samples above the LLOQ demonstrating the potential of the assay to sensitively measure biochemical adherence in real-world patient samples. This method for detection of adherence has the potential to be a more objective measure that could be used in the future in the clinic but will require further studies to explore factors that may influence measurement of drug levels, such as clinical characteristics of patients.

Etanercept originator versus etanercept biosimilar for the treatment of rheumatoid arthritis as a first biologic: results from the BSRBR-RA.

OBJECTIVES: Etanercept biosimilars show comparable efficacy to their originators among biologic-naïve patients with RA in randomized controlled trials. Nationwide guidelines have obligated prescribing of etanercept biosimilars from 2016, resulting in significant cost savings. This analysis aimed to compare the effectiveness of etanercept originator vs etanercept biosimilar amongst biologic-naïve RA patients treated in routine clinical practice in the UK. METHODS: Biologic-naïve RA patients starting etanercept in the British Society for Rheumatology Biologics Register in Rhematoid Arthritis (BSRBR-RA) cohort study from 2010 were included. Data collected at start of therapy includes patient demographics and disease activity. Follow-up data includes changes in disease activity and anti-rheumatic therapy. Six- and 12-month primary outcomes include DAS for 28-joints (DAS28) remission, EULAR response and minimal clinically important difference in function. Etanercept drug survival was assessed using Kaplan-Meier and Cox regression, including reasons for treatment withdrawal. Multiple imputation accounted for missing data. Propensity-decile adjustment was used to account for confounding by indication. RESULTS: A total of 1806 biologic-naïve RA patients started etanercept: 1009 originator, 797 biosimilar. At 6 and 12 months, the proportion of patients achieving DAS28 remission and EULAR response were similar between treatments. During follow-up, 19% of originator patients switched onto etanercept biosimilar. Patients were censored at time of switch. Patients on originator were no more likely to stop therapy vs biosimilar; 71% of originator and 76% of biosimilar patients remained on therapy at 1 year. CONCLUSIONS: In one of the largest analyses of patients with RA, biologic-naïve RA patients treated with etanercept originator showed similar outcomes vs biosimilar using real-world data. Drug survival, and disease activity after 6 and 12 months of therapy, was similar between cohorts.