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Introduction JAK-inhibitors have emerged as a new treatment option for rheumatoid arthritis, with five molecules currently available in different parts of the world: tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib. These molecules have been the subject of numerous trials looking at their efficacy (how well they perform in controlled conditions) but also some observational studies from the general population to assess their effectiveness (how well treatment perform under real conditions). With each their own weaknesses and strengths, they give different but complementary information. Areas covered We will review what we can learn from trials and real-world studies on how effective JAK-inhibitors are in the treatment of rheumatoid arthritis. Expert opinion Trials of JAK-inhibitors have shown that JAK-inhibitors are efficacious for the treatment of rheumatoid arthritis. However, their main outcomes are not clinically meaningful as their aim is mainly the regulatory authorisation of the product. Real-world studies are important as they evaluate the real-life effectiveness of the compounds, however, they are scarce at the moment, mainly evaluating tofacitinib and of variable quality. Future high-quality studies are needed to assess the real-world effectiveness of JAK-inhibitors in a more complete manner.

Objectives Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally—UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild—to quantify the occurrence of selected comorbidities in patients with JIA. Methods Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. Results 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1–1.8%) and uveitis (15–19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). Conclusion This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Objective As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed. Methods Adolescents (ages 11-17 years) in the UK Childhood Arthritis Prospective Study (CAPS) self-completed an adolescent Childhood Health Assessment Questionnaire (CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents answered the proxy-completed CHAQ. Those children with at least 2 simultaneously completed questionnaires at initial presentation or 1 year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modeling. A previously developed IRT model from the Pharmachild-NL registry from The Netherlands was validated in CAPS participants. Agreement and correlations between IRT-scaled functional ability scores were tested using intraclass correlations and Wilcoxon's signed rank tests. Results In 303 adolescents, the median age at diagnosis was 13 years, and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity, and the fact that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled in CAPS and Pharmachild-NL (maximum item residual 0.08). Significant differences were no longer evident between IRT-scaled HAQ and CHAQ scores. Conclusion IRT modeling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. IRT modeling facilitates the ongoing assessment of function as adolescents transfer from pediatric clinics to adult services.

Objectives This systematic review aims to summarize rates of adverse events (AEs) in patients with RA or inflammatory arthritis starting MTX as monotherapy or in combination with other csDMARDs, and to identify reported predictors of AEs. Methods Three databases were searched for studies reporting AEs in MTX-naïve patients with RA. Randomized controlled trials (RCTs) and observational cohort studies were included. Prevalence rates of AEs were pooled using random effects meta-analysis, stratified by study design. Results Forty-six articles (34 RCTs and 12 observational studies) were identified. The pooled prevalence of total AEs was 80.1% in RCTs (95% CI: 73.5, 85.9), compared with 23.1% in observational studies (95% CI: 12.3, 36.0). The pooled prevalence of serious AEs was 9.5% in RCTs (95% CI: 7.4, 11.7), and 2.1% in observational studies (95% CI: 1.0, 3.4). MTX discontinuation due to AEs was higher in observational studies (15.5%, 95% CI: 9.6, 22.3) compared with RCTs (6.7%, 95% CI: 4.7, 8.9). Gastrointestinal events were the most commonly reported AEs (pooled prevalence: 32.7%, 95% CI: 18.5, 48.7). Five studies examined predictors of AEs. RF status, BMI and HAQ score were associated with MTX discontinuation due to AEs; ACPA negativity, smoking and elevated creatinine were associated with increased risk of elevated liver enzymes. Conclusion The review provides an up-to-date overview of the prevalence of AEs associated with MTX in patients with RA. The findings should be communicated to patients to help them make informed choices prior to commencing MTX.

Methotrexate (MTX) is a common first-line treatment for new-onset rheumatoid arthritis (RA). However, MTX is ineffective for 30–40% of patients and there is no way to know which patients might benefit. Here, we built statistical models based on serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on-drug) to investigate if MTX response (by 6 months) could be predicted. Patients about to commence MTX treatment for the first time were selected from the Rheumatoid Arthritis Medication Study (RAMS). Patients were categorised as good or non-responders following 6 months on-drug using EULAR response criteria. Serum lipids were measured using ultra‐performance liquid chromatography–mass spectrometry and supervised machine learning methods (including regularized regression, support vector machine and random forest) were used to predict EULAR response. Models including lipid levels were compared to models including clinical covariates alone. The best performing classifier including lipid levels (assessed at 4 weeks) was constructed using regularized regression (ROC AUC 0.61 ± 0.02). However, the clinical covariate based model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.68 ± 0.02). Pre- or early-treatment serum lipid profiles are unlikely to inform classification of MTX response by 6 months with performance adequate for use in RA clinical management.

Objectives To describe how many people with RA reduce their baseline physical activity level over the first year of MTX treatment, and which factors predict this. Methods Data came from the Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of people with early RA starting MTX. Participants reported demographics and completed questionnaires at baseline, and 6 and 12 months, including reporting the number of days per week they performed ≥20 min of physical activity, coded as none, low (1–3 days) or high (4–7 days). The physical activity levels of participants over 12 months are described. Predictors of stopping physical activity were assessed using multivariable logistic regression. Results In total, 1468 participants were included [median (interquartile range) age 60 (50, 69) years; 957 (65.2%) women]. At baseline, the physical activity levels of the people with RA were: none = 408 (27.8%), low = 518 (35.3%) and high = 542 (36.9%). Eighty percent of participants maintained some physical activity or began physical activity between assessments (baseline to 6 months = 79.3%, 6 months to 12 months = 80.7%). In total, 24.1% of participants reduced physical activity and 11.3% of participants stopped performing physical activity between baseline and 6 months (6 months to 12 months: 22.6% and 10.2%, respectively). Baseline smoking, higher disability and greater socioeconomic deprivation were associated with stopping physical activity. Conclusion Many people with early RA were not performing physical activity when starting MTX, or stopped performing physical activity over the first year of treatment. These people may require interventions to stay active. These interventions need to be mindful of socioeconomic barriers to physical activity participation.

Objectives To describe the illness perceptions of patients with RA over the first year of MTX treatment, and the association between illness perceptions and outcomes. Methods Data came from the Rheumatoid Arthritis Medication Study (RAMS), a UK multicentre cohort study of RA patients starting MTX for the first time. Patients were assessed at baseline, and at 6 and 12 months. Patients completed the Brief Illness Perception Questionnaire (B-IPQ) at each assessment, as well as other patient-reported outcomes (PROs). The inflammation score (2-component DAS28) was calculated. Subgroups of patients with similar trajectories across the eight (B-IPQ) items were identified using a latent class growth model. Predictors of group membership were identified using multinomial logistic regression. Associations between subgroups and PROs over follow-up were assessed using linear mixed models. Results Three subgroups were identified in the analysis population (N = 1087): Positive illness perceptions (N = 322), Negative illness perceptions (N = 534) and Improvers (N = 231) who switched from negative to positive illness perceptions over follow-up. Baseline disability was associated with group membership [Positive vs Negative: relative risk ratio (RRR) 0.37, 95% CI: 0.25, 0.54; Improvers vs Negative: RRR 0.60, 95% CI: 0.43, 0.83], as were other PROs (pain, fatigue, anxiety, depression). The Negative group had worse disability, pain and fatigue over follow-up compared with the other groups, controlling for inflammation. Conclusion Negative illness perceptions are associated with poor PROs over time. The Improvers subgroup illustrated that illness perceptions can change in RA. Illness perceptions represent a potential therapeutic target that should be assessed using randomized trials.

Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.

ObjectivesWork is an important health outcome. This study aimed to identify predictors of work loss, absenteeism and presenteeism over 1 year in RA patients commencing treatment with MTX or biologics.MethodsPatients aged 18–65 years in full/part-time employment from two UK prospective cohorts were included: MTX-starters = Rheumatoid Arthritis Medication Study; and biologic-starters = Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate. Presenteeism and absenteeism were assessed using the RA-specific Work Productivity Survey at baseline, and 6 and 12 months. Potential predictors including baseline age, gender, clinical measures (e.g. disability, pain, fatigue), psychological distress, occupation and EULAR response from baseline to 6 months were investigated.ResultsA total of 51/463 MTX-starters and 30/260 biologic-starters left work over 12 months. Higher baseline psychological distress in MTX-starters [odds ratio (OR) 1.1 (95% CI: 1.0, 1.1)] and higher disability in biologic-starters [OR 3.5 (95% CI: 1.4, 8.6)] predicted work loss. Some 16.1% of patients reported sick-leave, which was predicted by disability [OR (95% CI): MTX-starters: 1.5 (0.9, 2.3); biologic-starters: 2.4 (1.1, 5.2)]. Median presenteeism scores were very low (minimal interference) in both cohorts. Higher fatigue for MTX starters [incidence rate ratio 1.2 (95% CI: 1.0, 1.4)] and higher disability in biologic-starters (incidence rate ratio 1.4 (95% CI: 1.1, 1.7)] predicted presenteeism. Good EULAR response was associated with lower absenteeism and presenteeism in both cohorts.ConclusionPatients with RA still face significant limitations regarding their ability to work. Disability and EULAR response were the main predictors of work outcomes, emphasizing the need to control the disease and the importance of function in enabling work participation.

ObjectiveTo develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA).MethodsAn EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A–D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0–10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members.ResultsTwo overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4–9.6).ConclusionsThese PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.

Summary Background Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. Methods In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behcet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. Findings Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behcet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. Interpretation Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. Funding American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Despite the success of TNF-inhibitor therapy in rheumatoid arthritis treatment, up to 40% of patients fail to respond adequately. This study aimed to identify transcriptome-based biomarkers of adalimumab response in rheumatoid arthritis (RA) to aid timely switching in non-responder patients and provide a better mechanistic understanding of the pathways involved in response/non-response.The Affymetrix Human Transcriptome Array 2.0 (HTA) was used to measure the transcriptome in whole blood at pre-treatment and at 3 months in EULAR good- and non-responders to adalimumab therapy. Differential expression of transcripts was analysed at the transcript level using multiple linear regression. Differentially expressed genes were validated in independent samples using OpenArray™ RT-qPCR.In total, 813 transcripts were differentially expressed between pre-treatment and 3 months in adalimumab good-responders. No significant differential expression was observed between good- and non-responders at either time-point and no significant changes were observed in non-responders between time-points. OpenArray™ RT-qPCR was performed for 104 differentially expressed transcripts in good-responders, selected based on magnitude of effect or p value or based on prior association with RA or the immune system, validating differential expression for 17 transcripts.An early transcriptome signature of DAS28 response to adalimumab has been identified and replicated in independent datasets. Whilst treat-to-target approaches encourage early switching in non-responsive patients, registry evidence suggests that this does not always occur. The results herein could guide the development of a blood test to distinguish responders from non-responders at 3 months and support clinical decisions to switch non-responsive patients to an alternative therapy.

Objective: To describe the frequency and predictors of nonserious infections (NSI) and compare incidence across biologic agents within the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA).Methods: The BSRBR-RA is a prospective observational cohort study. An NSI was defined as an infection that did not require hospitalization or intravenous therapy. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered “at risk” from the date of initiation of biologic treatment for up to 3 years. Drug exposure was defined by agent: tumor necrosis factor inhibitor (TNFi), interleukin-6 (IL-6) inhibitor, B cell depletion (rituximab), or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone. A multiple-failure Cox model was used with multivariable adjustment. Missing data were addressed using multiple imputation.Results: There were 17,304 NSI in 8,145 patients, with an event rate of 27.0 per person per year (95% confidence interval [95% CI] 26.6–27.4). Increasing age, female sex, comorbidity burden, glucocorticoid therapy, higher Disease Activity Score in 28 joints, and higher Health Assessment Questionnaire disability index were associated with an increased risk of NSI. There was a significant reduction in NSI risk with csDMARDs compared to biologic treatments. Compared to TNFi, IL-6 inhibition and rituximab were associated with a higher NSI risk (adjusted hazard ratio 1.45 [95% CI 1.29–1.63] and adjusted hazard ratio 1.28 [95% CI 1.14–1.45], respectively), while the csDMARD cohort had a lower risk (adjusted hazard ratio 0.64 [95% CI 0.59–0.70]). Within the TNFi class, adalimumab was associated with a higher NSI risk than etanercept (adjusted hazard ratio 1.11 [95% CI 1.05–1.17]).Conclusion: NSI occur frequently in RA, and predictors mirror those reported with serious infections. All biologics are associated with a greater risk of NSI, with differences observed between agents. While unmeasured confounding must be considered, the magnitude of effect is large, and a relationship between NSI and targeted immunomodulatory therapy likely exists.

Objective To evaluate whether polypharmacy is associated with treatment response and serious adverse events (SAEs) in patients with RA using data from the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study of biologic therapy starters and a DMARD comparator arm. A logistic regression model was used to calculate the odds of a EULAR ‘good response’ after 12 months of biologic therapy by medication count. Cox proportional hazards models were used to identify risk of SAEs. The utility of the models were compared with the Rheumatic Disease Comorbidity Index using Receiver Operator Characteristic and Harrell’s C statistic. Results The analysis included 22 005 patients, of which 83% were initiated on biologics. Each additional medication reduced the odds of a EULAR good response by 8% [odds ratios 0.92 (95% CI 0.91, 0.93) P < 0.001] and 3% in the adjusted model [adjusted odds ratios 0.97 (95% CI 0.95, 0.98) P < 0.001]. The Receiver Operator Characteristic demonstrated significantly greater areas under the curve with the polypharmacy model than the Rheumatic Disease Comorbidity Index. There were 12 547 SAEs reported in 7286 patients. Each additional medication equated to a 13% increased risk of an SAE [hazard ratio 1.13 (95% CI 1.12, 1.13) P < 0.001] and 6% in the adjusted model [adjusted hazard ratio 1.06 (95% CI 1.05, 1.07) P < 0.001]. Predictive values for SAEs were comparable between the polypharmacy and Rheumatic Disease Comorbidity Index model. Conclusion Polypharmacy is a simple but valuable predictor of clinical outcomes in patients with RA. This study supports medication count as a valid measure for use in epidemiologic analyses.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

ObjectiveTo investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA).MethodsWe analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders.ResultsOf 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity.ConclusionsPeople with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

Background/Aims In the real-world, tocilizumab is prescribed to a population of patients different from those prescribed TNF-inhibitors, often older with longer disease duration, worse functional status and more previous b- or tsDMARDs. The aim of this study was to evaluate if and how the risk of serious infection on tocilizumab and other bDMARDs differs when stratifying by line of therapy in a real-world population of rheumatoid arthritis patients. Methods We included patients registered in the BSRBR-RA treated with tocilizumab, etanercept, adalimumab, infliximab, certolizumab, abatacept or rituximab, including biosimilars. Primary outcome was the occurrence of a serious infection (defined as infection requiring hospitalisation, intravenous antibiotics or resulting in death). Primary covariate of interest was line of therapy (from first to fifth line of therapy). Every change to another b- or tsDMARD was considered a new line of therapy, but not a change between a bio-original and a biosimilar. Hazard ratios (HR) of serious infections were estimated using an inverse probability weighted Cox regression, based on a propensity score including baseline patient and disease characteristics, and adjusting for time in study (see table). The reference group was etanercept, which included the highest number of patients. Treatment exposure was analysed without and with stratification by line of therapy. Results A total of 33,916 treatment courses were included (Table) contributing to 62,532 years of follow-up. Compared to etanercept, participants starting abatacept, tocilizumab and rituximab were older, had more previous bDMARDs, longer disease duration and more comorbidities. The crude HR of serious infections were higher with infliximab and adalimumab, lower with certolizumab and rituximab, and not significantly different for abatacept and tocilizumab compared to etanercept. After adjustment, HR of serious infections were higher with tocilizumab, adalimumab and infliximab. However, when stratified by line of therapy, HR were no longer significantly different compared to etanercept for tocilizumab, adalimumab and infliximab for most lines of therapy. Conclusion Whilst initially there appears to be a difference in rates of serious infections between biologic therapies, line of therapy may be a confounding factor when comparing the risk of serious infections between bDMARDs. Disclosure K. Lauper: Honoraria; Gilead-Galapagos. Grants/research support; AbbVie. Other; AbbVie, Pfizer. L. Kearsley-Fleet: None. R. Davies: None. K. Watson: None. M. Lunt: None. K.L. Hyrich: Honoraria; AbbVie. Grants/research support; Pfizer, BMS.

Background Despite the success of TNF-inhibitor therapy in rheumatoid arthritis treatment, up to 40% of patients fail to respond adequately. This study aimed to identify transcriptome-based biomarkers of adalimumab response in rheumatoid arthritis (RA) to aid timely switching in non-responder patients and provide a better mechanistic understanding of the pathways involved in response/non-response. Methods The Affymetrix Human Transcriptome Array 2.0 (HTA) was used to measure the transcriptome in whole blood at pre-treatment and at 3 months in EULAR good- and non-responders to adalimumab therapy. Differential expression of transcripts was analysed at the transcript level using multiple linear regression. Differentially expressed genes were validated in independent samples using OpenArray™ RT-qPCR. Results In total, 813 transcripts were differentially expressed between pre-treatment and 3 months in adalimumab good-responders. No significant differential expression was observed between good- and non-responders at either time-point and no significant changes were observed in non-responders between time-points. OpenArray™ RT-qPCR was performed for 104 differentially expressed transcripts in good-responders, selected based on magnitude of effect or p value or based on prior association with RA or the immune system, validating differential expression for 17 transcripts. Conclusions An early transcriptome signature of DAS28 response to adalimumab has been identified and replicated in independent datasets. Whilst treat-to-target approaches encourage early switching in non-responsive patients, registry evidence suggests that this does not always occur. The results herein could guide the development of a blood test to distinguish responders from non-responders at 3 months and support clinical decisions to switch non-responsive patients to an alternative therapy.

Altres ajuts: Department of Health via the National Institute for Health Research (NIHR); St Thomas' NHS Foundation Trust; King's College London; NIHR Manchester Biomedical Research Centre; Psoriasis Association. Wellcome Senior Research Fellowship in Clinical Science (205039/Z/16/Z); Health Data Research UK (grant no. LOND1); Health Data Research UK (grant no. MR/S003126/1); UK MRC, Engineering and Physical Sciences Research Council; Economic and Social Research Council; Department of Health and Social Care (England); Chief Scientist Office of the Scottish Government Health; Social Care Directorates; Health and Social Care Research and Development Division (Welsh Government); Public Health Agency (Northern Ireland); British Heart Foundation; Wellcome Trust; NIHR Academic Clinical Lectureship through the University of Manchester; NIHR Emeritus Senior Investigator (MR/101 1808/1); NIHR Manchester Biomedical Research Centre. Background: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. Objectives: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. Methods: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. Results: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. Conclusions: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Objectives To compare cervical screening attendance and cytology (high- and low-grade cervical dysplasia [HGCD and LGCD]) between women with RA and the English general population and between biologic DMARD (bDMARD)-naïve and exposed women. Methods The British Society for Rheumatology Biologics Register for RA (BSRBR-RA), a national prospective study of RA treatment outcomes, was linked to the National Health Service Cervical Screening Programme, providing data for 12 785 women to compare with national screening data. Rates of HGCD/LGCD were compared with rates of negative smears using risk difference calculations between BSRBR-RA and national statistics. Within the BSRBR-RA, coverage was compared between those with low and high physical disability scores, while coverage and cytology results were compared between bDMARD-naïve and -exposed RA patients. Results The mean 5 year screening coverage was significantly higher in BSRBR-RA (83%) compared with the general population (79%), but lower in women with high disability (78%) compared with lesser disability (85%). Risk differences for HGCD were lower in the BSRBR-RA compared with national statistics, whereas risk differences for LGCD were higher. There was no statistically significant difference in the rates of HGCD or LGCD between bDMARD-exposed and -naïve women. Conclusion This first-ever British analysis of cervical screening rates in RA has shown that women with RA have higher screening rates than the general population. Disability negatively impacts attendance, but treatment type does not. Women with RA did not have an increased risk of HGCD compared with national statistics, which was also not influenced by bDMARD exposure.

Summary Background Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course. Methods In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician's global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. Finding Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitis-related JIA and lower socioeconomic status, compared with those in other groups. Interpretation Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician's global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA. Funding Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and National Institute for Health Research.

ObjectivesRegistry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse COVID-19 outcomes compared to patients receiving no systemic treatments. We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation.MethodsOnline surveys were completed by individuals with Rheumatic and Musculoskeletal Diseases (RMD) (UK only) or psoriasis (globally) between 4th May and 7th September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterised international variation in a mixed effects model.ResultsOf 3,720 participants (2,869 psoriasis, 851 RMD) from 74 countries, 2,262 (60.8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term ‘shielding’). A greater proportion of those receiving targeted therapies (biologics and JAK inhibitors) reported shielding compared to those receiving no systemic therapy (adjusted odds ratio [OR] 1.63, 95% CI 1.35-1.97) and standard systemic agents (OR 1.39, 95% CI 1.22-1.56). Shielding was associated with established risk factors for severe COVID-19 (male sex [OR 1.14, 95% CI 1.05-1.24], obesity [OR 1.38, 95% CI 1.23-1.54], comorbidity burden [OR 1.43, 95% CI 1.15-1.78]), a primary indication of RMD (OR 1.37, 95% CI 1.27-1.48) and a positive anxiety or depression screen (OR 1.57, 95% CI 1.36-1.80). Modest differences in the proportion shielding were observed across nations.ConclusionsGreater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk mitigation strategies and may help inform updated public health guidelines as the pandemic continues.Key messagesWhat is already known about this subject?At the beginning of the COVID-19 pandemic, patients with immune mediated inflammatory diseases (IMIDs) on targeted systemic immunosuppressive therapy were considered to be at higher risk of severe COVID-19. Subsequent registry data suggest that this may not the case.What does this study add?Here we characterise shielding behaviour in patients with IMIDs from a global survey. We identified that targeted systemic therapy associates with increased shielding behaviour, as do demographic risk factors for severe COVID-19 including male gender and obesity.Shielding behaviour varies across nations, albeit modestly when case-mix is taken into account.How might this impact on clinical practice or future developments?Variable shielding behaviour amongst patients with IMIDs may be an important confounder when considering differential COVID-19 risk between therapy types, so should be accounted for in analyses where possible.

We thank Giollo and colleagues for their correspondence acknowledging the challenges of understanding those risk factors which contribute to severe outcomes in patients with underlying rheumatic musculoskeletal diseases (RMDs) who acquire the novel SARS-CoV‐2 infection.1 In their short case series, they highlight the balance and relative importance between disease activity and dose of glucocorticoid therapy, two factors which are highly linked within an individual. It is already known that both disease activity and glucocorticoid dose are independent risk factors for serious infection in patients with RMD, such as rheumatoid arthritis and systemic lupus erythematosus,2–4 as …

We thank Gyorfi et al for their correspondence.1 The case they present demonstrates a potentially important point that was reported in our manuscript2: the effect of systemic glucocorticoids may worsen outcomes in patients with rheumatic disease. However, as has been highlighted recently by the results of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial, systemic glucocorticoids may have a role to play in treating COVID-19.3 Noteworthy, in the RECOVERY trial, dexamethasone (6 mg daily for 10 days) only reduced deaths in the patients that were ventilated (one-third reduction) or receiving oxygen (one-fifth reduction) but no benefit was seen among those patients who did not require respiratory support; moreover, the trial did not study …

Background Patients with rheumatoid arthritis (RA) are at an increased risk of infection. Most attention has been given to serious infections, but these are the tip of the iceberg. Non-serious infections (NSI) are far more frequent, and although not life-threatening, have potential to impact treatment outcomes (drug survival) and quality of life. Our objective was to describe frequency of NSI and compare incidence of NSI by biologic drug within the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. NSI was identified as not requiring hospitalisation, intravenous therapy or leading to disability or death. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered ‘at risk’ from the date of commencing biologic treatment for 3 years. Drug exposure was defined by agent; TNF inhibitor, IL-6 inhibitor, anti-CD20 or csDMARD only. To account for a high frequency of events, a multiple-failure Cox model was used. Multivariable adjustment included age, gender, DAS28-ESR, HAQ-DI, disease duration, smoking, steroid usage, year recruited to BSRBR-RA, line of biologic therapy and cumulative infection number. Results There were 17,304 NSI in 10,099 patients, with an event rate of 27.0 per year (95% CI 26.6 to 27.4). Increasing age, female gender, comorbidity burden, corticosteroid therapy, DAS28 and HAQ-DI were associated with an increased risk of NSI. The rate of NSI was numerically lowest with csDMARDs. Compared to TNFi, IL-6 inhibitor had a higher risk of NSI, whilst the csDMARD cohort had a lower risk. Between the TNFi agents, adalimumab had a higher risk than etanercept (Table 1). Conclusion These results confirm that NSI is a frequent occurrence for patients, which historically has received little attention in research literature. The data suggest biologics increase the risk of NSI, especially IL-6 inhibition. Whilst unmeasured confounding must be considered, the magnitude of effects are large and it seems likely that a causal link between targeted immunosuppression and NSI risk exists. Further research is needed to understand the impact of NSI on clinical outcomes including drug survival and quality of life. Disclosures K. Bechman: None. K. Halai: None. S. Norton: None. A.P. Cope: None. K.L. Hyrich: Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway: Honoraria; for speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background Tocilizumab is an IL-6 receptor humanised monoclonal antibody treatment option in rheumatoid arthritis (RA) who have not responded or are intolerant of disease modifying anti-rheumatic drugs (DMARDs) or other biologics. Tocilizumab was available initially as an intravenous preparation, dosed according to weight, and more recently as a subcutaneous (SC) preparation given at 162mg/weekly irrespective of body weight. Obesity is highly prevalent in RA and there has been concern that starting or switching patients to SC tocilizumab could reduce its effectiveness in those patients with a higher body weight. The objective of the current study is to investigate the relationship between body weight and DAS28 response at 6 months in tocilizumab naïve RA patients starting SC tocilizumab. Methods The study population comprised RA subjects recruited to the BSRBR-RA up to 30/11/2018 commencing SC tocilizumab for the first time. Patients had to be tocilizumab naïve and have at least one six monthly study follow-ups recorded after starting tocilizumab. Baseline characteristics at point of starting tocilizumab are described. Linear regression, fully adjusted for relevant confounders, was used to investigate the relationship between change in DAS28 score from baseline to six months and body weight per ten kilograms (kg), and in a separate analysis, as BMI category. Multiple imputation was used to handle missing data. Results Three hundred and fifteen patients starting SC tocilizumab were eligible for analysis. The median age was 60 years, majority were female, and had median disease duration of 11 years at baseline. Seventy percent had prior biologic exposure. Median weight was 76kg, and the majority of patients were categorised as normal weight (37%) or pre-obesity (31%) according to BMI. Median DAS28 score was 5.5 at start of treatment with median improvement after 6-months of 2.0 units. The fully adjusted linear regression model showed no association between body weight or BMI and change in DAS28 score at six months (Table 1). Conclusion Data from this study show that body weight does not appear to affect initial response to SC tocilizumab. This is reassuring given that patients are likely to be given subcutaneous tocilizumab due to ease of administration and reduced hospital costs. Disclosures R. Davies None. A. Vivekanantham None. M. Lunt None. K. Watson None. K.L. Hyrich None. J. Bluett None.

Background In 2017, a new class of oral disease modifying anti-rheumatic drugs (DMARDs), janus kinase inhibitors (JAKi), were licensed for rheumatoid arthritis (RA): baricitinib and tofacitinib. In the UK, they are approved for use in patients with high disease activity with or without methotrexate, following failure of conventional synthetic (cs) DMARDs or biologic DMARDs, the latter when rituximab is contraindicated. As a new therapy option, it is currently unclear how and when these drugs are being prescribed in patients with RA. This analysis aims to describe the characteristics of patients starting JAKi and registered with the BSRBR-RA. Methods The BSRBR-RA aims to capture exposure and outcome data in patients with RA receiving biologics, biosimilars and targeted synthetic DMARDs. At the start of therapy, demographic and clinical data, including past treatment data, are collected. Characteristics of all patients receiving a JAKi for the first time with data recorded in the BSRBR-RA up to 31/03/2019 are described. Results To 31/03/2019, 698 patients in the BSRBR-RA have been treated with a JAKi; 596 patients baricitinib and 110 tofacitinib (Table 1). A quarter of patients received a JAKi with no prior biologic exposure; 148 (25%) baricitinib and 16 (15%) tofacitinib. Of these, 15% had a prior malignancy history. Of those with prior biologic exposure, the median number of previous biologics was 3 (IQR 2-4), the majority had prior TNFi (91%) or rituximab (51%), and 50% were receiving concurrent methotrexate. Conclusion To date, more patients have been recruited starting baricitinib than tofacitinib, likely owing to the later licensing of tofacitinib. Two groups are emerging with a quarter of patients receiving JAKi immediately after csDMARDs and a majority as a later stage alternative following multiple biologics. Further recruitment and follow-up patients will allow for analysis of real-world safety and effectiveness, but differences in patient characteristics will need to be considered in any comparative effectiveness analyses. Disclosures L. Kearsley-Fleet None. R. Davies None. K. Watson None. M. Lunt None. K.L. Hyrich Honoraria; AbbVie. Grants/research support; UCB, Pfizer, BMS.

Background There is an established increase risk of infection in rheumatoid arthritis (RA). Most published data examine serious events, which affect 3-5% of patients annually. Approximately half of the patients experience non-serious infection, which does not require parental antibiotics or hospitalisation. Sinusitis events affecting patients on biologics (particularly TNF inhibition) have been observed but not well described, with a prevalence of 2-17%. Sinusitis is associated with treatment discontinuation and surgical interventions. We aim to describe the rates of sinusitis with different RA treatment strategies and provide estimates of risk difference. Methods The population was adults with RA, enrolled in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis registry (BSRBR-RA) during the first 3 years of study on biologic treatment. The predictor was treatment strategy at the time of event (csDMARD only, TNF inhibitors, IL-6 inhibitors and anti-CD20). The primary outcome was sinusitis according to MeddraPT codes reported by patients (via patient diary) or clinician (on an adverse event form). A multi-failure Cox survival model was used to compare risk across treatment groups. A multivariate model adjusted for confounders (age, gender, entry year in BSRBR-RA, disease duration, baseline disease activity by DAS-28, HAQ, comorbidities, smoking status and steroid use. Results 23,584 patients were included, contributing to a total of 64,035 patient-years of follow up. There were 797 infective events in 580 patients. This corresponded to a rate of 0.95 per year (95% CI 0.87 to 0.1.02). The sinusitis rate was numerically highest with anti-CD20 (Rituximab) and lowest with csDMARDs (Table 1). In the adjusted Cox proportional hazard model, all 3 biologics strategies had a significantly higher rate of sinusitis compared to csDMARD cohort; (TNFi 2.76 (95%CI 1.85 to 4.12); IL-6R 2.51 (1.00 to 6.29); anti-CD20 3.14 (1.46 to 6.72). Conclusion Sinusitis is more common in patients prescribed biologics compared to the csDMARD. The highest rate was seen with rituximab. This would fit biologically, as the primary immunodeficiency phenotype of recurrent sinusitis aligns with antibody defects e.g. common variable immunodeficiency. However, it is interesting to observe that sinusitis is more common across the treatment classes. Disclosures K. Halai None. K. Bechman None. S. Norton None. A.P. Cope None. K.L. Hyrich Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway Honoraria; or speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background For patients with rheumatoid arthritis (RA), introduction of early, effective therapy has consistently been shown to improve long-term outcomes. Low-dose methotrexate (MTX) is commonly prescribed as first-line treatment for RA. However, MTX is not effective for a large minority of patients and there is currently no way to determine ahead of therapy which patients are most likely to benefit. Metabolomics and lipidomics are emerging approaches for studying patient stratification in RA and have the potential to identify disease processes that underpin treatment outcomes. Here we apply state-of-the-art machine learning algorithms to predict MTX treatment response, by testing serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on drug) to predict MTX response by 6 months. Methods This study included patients from the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre one-year prospective observational study investigating predictors of response to MTX in patients with RA. Since 2008, patients who are about to start MTX for the first time are asked to provide demographic and clinical data, as well as blood samples to permit DNA, RNA and serum-based biomarker studies. Patients about to commence MTX treatment were followed longitudinally and those categorised as good or non-responders following 6 months on-drug using EULAR response criteria were analysed. Serum lipid levels were measured at pre-treatment and following 4 weeks on drug using ultra-performance liquid chromatography tailored for complex lipid analysis, coupled to mass spectrometry. State-of-the-art supervised machine learning methods were then applied to predict EULAR response at 6 months. Models including lipid levels were compared to models including clinical covariates (including: MTX start dose, steroid use at inclusion, BMI, number of swollen joints, number of tender joints, CRP levels, patients’ assessment of their overall wellbeing, gender, age-at-inclusion, age-at-onset, disease duration, HAQ score and pre-treatment smoking habits). Results Following quality control, 3,366 features (1,060 in negatively-charged mode and 2,306 in positive mode) were available for analysis at pre-treatment and 4 weeks from 100 RA patients categorised as good (GR, n = 50) or poor (NR, n = 50) responders to MTX following 6 months on drug. The best model performance for the classifier including clinical covariates was observed using L1/L2-regularised logistic regression (ROC AUC 0.68 ± 0.02). However, the clinical covariate model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.61 ± 0.02). Conclusion These data do not support the utility of early treatment lipidomic monitoring in routine clinical practice in patients started on MTX for their RA. Disclosures M. Maciejewski: Shareholder/stock ownership; owns stock or stock options in Pfizer. C. Sands None. N. Nair None. S. Ling None. S. Verstappen None. K. Hyrich None. A. Barton None. D. Ziemek Shareholder/stock ownership; owns stock or stock options in Pfizer. M. Lewis None. D. Plant None.

Summary Background Information is scarce about biological disease-modifying antirheumatic drug (DMARD) switching patterns in children and young people (aged ≤16 years) with juvenile idiopathic arthritis in an era of many biologic therapies. The best choice of biologic to use if the first biological DMARD is not beneficial also remains unclear. We aimed to quantify and characterise biologic switching patterns in children and young people with juvenile idiopathic arthritis, and to compare the effectiveness of using a second tumour necrosis factor inhibitor (TNFi) versus non-TNF is following failure of a first TNFi biologic in routine clinical practice. Methods Our study population comprised patients with juvenile idiopathic arthritis who were enrolled in two parallel UK cohort studies (the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study [BSPAR-ETN] and the Biologics for Children with Rheumatic Diseases [BCRD] study) between Jan 1, 2004, and April 11, 2019. Data on disease characteristics and DMARD therapy were collected at the time of initiation of a first biologic, at 6 months, at 1 year, and annually thereafter. Biologic switching patterns were described in all patients who started their first biologic from Jan 1, 2010, onwards. Among patients who started treatment with their first biologic from Jan 1, 2004, onwards, had polyarticular course juvenile idiopathic arthritis (extended oligoarthritis or polyarthritis [positive or negative for rheumatoid factor]), and who had started a second biologic, we assessed changes in outcome variables at 6 months compared with baseline and compared the proportion of patients who achieved an American College of Rheumatology Pediatric (ACR Pedi) 90 response and minimal disease activity at 6 months on the basis of the class of the second biologic (a second TNFi vs non-TNFi biologic). Changes in outcome variables at 6 months were compared using linear regression or logistic regression, adjusted for propensity quintiles to account for confounding by indication. We used multiple imputation to account for missing data. Findings Between Jan 1, 2004, and April 11, 2019, 2361 patients were enrolled on initiation of biologic therapy. From Jan 1, 2010, onwards, 1152 patients started their first biologic, most of whom started treatment with TNFis (1050 [91%]). The median follow-up was 2·2 years (IQR 1·1–3·8). During this time, 270 (23%) of 1152 patients started a second biologic, 61 (5%) started a third biologic, and 11 (1%) started a fourth biologic. Among 240 patients with polyarticular-course juvenile idiopathic arthritis, 194 (81%) started a second TNFi and 46 (19%) started a non-TNFi after an initial TNFi had failed. Choice of second treatment (second TNFi vs non-TNFi biologic) did not affect the proportion of patients who achieved an ACR Pedi 90 response (adjusted odds ratio [OR] 2·5, 95% CI 0·8–7·9; p=0·11) or minimal disease activity (adjusted OR 1·6, 95% CI 0·6–3·8; p=0·33). Interpretation For many children and young people with juvenile idiopathic arthritis, treatment with a first or second biologic is not beneficial. We found no evidence that switching to a second non-TNFi biologic was more beneficial than a second TNFi. Funding Versus Arthritis and The British Society for Rheumatology.

Background Until 2018, NICE guidance recommended the use of a combination of disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX), in the initial management of people with rheumatoid arthritis (RA). In 2018 the guideline was updated to recommend monotherapy with MTX due to uncertainties in the evidence for combination therapy. However, it remains a requirement for progression onto any biologic that the patient should have persistent high disease activity and/or have intolerance to, a minimum of two DMARDs. The aim of this study was to understand the association between initial treatment strategy and EULAR response at 6 months. Methods This analysis included patients recruited to the longitudinal observational Rheumatoid Arthritis Medication Study (RAMS) in the UK who were DMARD naïve and had symptoms for less than 1 year. Patients were defined as either starting MTX monotherapy or MTX in combination with another DMARD (6 weeks either side of MTX start date) and categorised into EULAR non responders or moderate/ good responders after 6 months. A logistic regression model was applied to test the association between initial treatment strategy and EULAR response at 6 months, adjusting for confounders. Results A total of 948 participants were included in the analysis. MTX monotherapy was prescribed in 72% (n = 678) of patients and combination therapy was prescribed in 28% (n = 270) of patients, the majority of whom received MTX plus hydroxychloroquine (HCQ) (n = 236, 87%). There was no significant difference between the MTX monotherapy and combination therapy groups in EULAR response at 6-months (adjusted odds ratio [aOR] 0.77, 95% CI 0.53 to 1.14). Conclusion In this large UK observational study investigating the effect of treatment strategy within the first 6 weeks of presentation and treatment response at 6 months, there was no significant difference between combination DMARD therapy and MTX monotherapy on EULAR response. Most patients received MTX in combination with HCQ, for which little evidence exists. Disclosures S. Wood None. K. Hyrich Consultancies; ABBVIE. Grants/research support; BMS, PFIZER, UCB. S. Verstappen None. D. Steinke None.

OBJECTIVE: To determine whether using a reweighted disease activity score that better reflects joint synovitis, i.e., the 2-component Disease Activity Score in 28 joints (DAS28) (based on swollen joint count and C-reactive protein level), produces more clinically relevant treatment outcome trajectories compared to the standard 4-component DAS28.METHODS: Latent class mixed modeling of response to biologic treatment was applied to 2,991 rheumatoid arthritis (RA) patients in whom treatment with a biologic disease-modifying antirheumatic drug was being initiated within the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort, using both 4-component and 2-component DAS28 scores as outcome measures. Patient groups with similar trajectories were compared in terms of pretreatment baseline characteristics (including disability and comorbidities) and follow-up characteristics (including antidrug antibody events, adherence to treatments, and blood drug levels). We compared the trajectories obtained using the 4- and 2-component scores to determine which characteristics were better captured by each.RESULTS: Using the 4-component DAS28, we identified 3 trajectory groups, which is consistent with previous findings. We showed that the 4-component DAS28 captures information relating to depression. Using the 2-component DAS28, 7 trajectory groups were identified; among them, distinct groups of nonresponders had a higher incidence of respiratory comorbidities and a higher proportion of antidrug antibody events. We also identified a group of patients for whom the 2-component DAS28 scores remained relatively low; this group included a high percentage of patients who were nonadherent to treatment. This highlights the utility of both the 4- and 2-component DAS28 for monitoring different components of disease activity.CONCLUSION: Here we show that the 2-component modified DAS28 defines important biologic and clinical phenotypes associated with treatment outcome in RA and characterizes important underlying response mechanisms to biologic drugs.

Objectives To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Methods Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. Results In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Conclusions Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.

Objectives To establish the rate of recurrent infection in RA patients recruited to the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis. Secondary objectives were to establish whether the organ class of index infection predicted future serious infection (SI). Methods Using data from the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis, a prospective observational cohort, we identified patients with at least one episode of SI. Incidence rates of SI, recurrent SI within the same organ class as the index infection and recurrent SI (of any class) were calculated. A Cox proportional hazards model was used to identify predictors of SI. Results In total, 5289 subjects with at least one SI contributing 19 431 patient-years follow-up were studied. The baseline annual rate of first SI was 4.6% (95% CI: 4.5, 4.7), increasing to 14.1% (95% CI: 13.5, 14.8) following an index infection. Respiratory infections were the most frequent (44% of all events). Recurrent infections mirrored the organ class of the index infection. Sepsis, increasing age and polypharmacy were significant predictors of infection recurrence in a fully adjusted model. The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent SI within 12 months, 19.7% (95% CI: 15.1, 25.7). Conclusion Recurrent infections in RA are common. Understanding patterns and predictors of recurrent infection together with the differential infection risk associated with immunosuppressive agents will help personalize RA care, tailor treatment choices better and mitigate against episodes of SI.

Key Points Question Is receipt of tumor necrosis factor (TNF) inhibitor monotherapy at the time of COVID-19 diagnosis associated with adverse COVID-19 outcomes compared with other treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs)? Findings In this cohort study of 6077 patients with IMIDs and COVID-19, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, or Janus kinase inhibitor monotherapy were each associated with significantly higher odds of hospitalization or death compared with TNF inhibitor monotherapy. Meaning This study’s findings support the continued use of TNF inhibitor monotherapy among individuals with IMIDs during the pandemic., Importance Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19–associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures The main outcome was COVID-19–associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P, This cohort study uses data from 3 international registries to examine the association between the receipt of tumor necrosis factor monotherapy and the risk of COVID-19–associated hospitalization or death among adult patients with immune-mediated inflammatory diseases.

Objectives. Anti-tumour necrosis factor antibody (anti-TNF) has revolutionised the treatment of rheumatoid arthritis (RA) and remission is now a realistic possibility for patients. Despite widespread use of anti-TNFs, predicting which patients are most likely to attain a sustained good response to these treatments remains challenging. Our objective was to undertake a systematic review of the literature to evaluate existing evidence for demographic and clinical factors associated with the achievement of sustained remission in individuals with RA treated with anti-TNF. Methods. EMBASE, MEDLINE and the Cochrane Controlled Trials Register were searched along with studies identified from reference lists. Quality of studies was assessed using Newcastle-Ottawa criteria. Meta-analysis was undertaken where unadjusted odds ratios were available for the same demographic or clinical factors from at least three studies. Results. Six studies were identified. Concomitant methotrexate use was associated with an increased likelihood of achieving sustained remission. Greater baseline disease activity, tender joint count, age, disease duration, baseline functional impairment and female gender were associated with reduced likelihood of achieving sustained remission. Conclusions. Factors predicting sustained remission are seldom reported. Evidence identified in this review supports current recommendations for methotrexate co-prescription and highlights the negative impact of particular clinical and demographic features on the likelihood of achieving optimal response to anti-TNF treatment. Sustained remission is clinically more relevant than point remission in RA. More widespread reporting of sustained remission will help clinicians set realistic expectations on likely long-term treatment efficacy and could be an important tool for identifying patients suitable for dose optimisation. This article is protected by copyright. All rights reserved.

Objective To identify different trajectories of disease activity in patients with RA following initiation of a first anti-TNF. Methods Patients with RA starting their first anti-TNF between 2001 and 2013 were selected from the British Society for Rheumatology Biologics Register for RA. Six-monthly DAS28-ESR scores were used to identify trajectories of disease activity using latent class modelling. Data were included for six follow-ups after registration (approximately 3 years). Subgroup analysis examined changes in disease activity profiles over time. Results A total of 14 436 patients with RA starting their first anti-TNF were enrolled between 2001 and 2013 (13 115 between 2001 and 2008, 1321 between 2010 and 2013). The mean number of DAS28-ESR scores was 3.5/patient (s.d. 2.1), with a mean of 184.9 days (s.d. 69.9) between scores. The DAS28-ESR nadir was achieved within 250 days of commencing anti-TNF, although apparent trajectory divergence emerged by first 6-monthly follow-up at 180 days. Four distinct response trajectories comprised the most stable model. Most patients fitted into ‘modest’ (7986 patients; 55.3%) or ‘substantial’ (4676 patients; 32.4%) response trajectories. Of the remainder, 1254 (8.7%) and 520 (3.6%) fitted ‘maximal’ and ‘minimal’ response trajectories, respectively. There was a significant (P < 0.01) increase in proportion achieving ‘maximal’ response between 2001–2008 and 2010–2013. Conclusion This is the largest study to identify long-term response trajectories with anti-TNF. By 6 months, longer-term trajectory profiles of DAS28 could already be identified, with many patients identified earlier. The majority of patients had persistent moderate response, equivalent to maintained DAS28-ESR moderate disease activity. The maximal response trajectory (equivalent to sustained DAS2-ESR remission) was only achieved by approximately one-third of patients.

ObjectivesIdentifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.MethodsDNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.ResultsIn the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.ConclusionThese data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.

Background Most research concerning biosimilar use in musculoskeletal diseases has been conducted in adults. Little to no data regarding the use of biosimilars in children and young people with juvenile idiopathic arthritis (JIA) exist. Our aim was to describe the characteristics of children and young people with JIA starting biosimilars in the United Kingdom (UK) with musculoskeletal diseases. Methods The Biologics for Children with Rheumatic Diseases (BCRD) study is an ongoing prospective UK study recruiting children and young people with JIA starting biologic therapies other than etanercept originator (followed in a separate parallel study) from 2010 onwards. Baseline information is collected via questionnaires completed by the treating physician or affiliated clinical research nurse. Follow-up data including disease activity measures and changes in drug therapy are collected at six months, one year and annually thereafter. From May-2015, data has been captured on anti-TNF biosimilars in the UK. Results To 18 June 2019, 159 patients had started a biosimilar; 84 (53%) infliximab (2 products), 60 (38%) etanercept (2 products), and 15 (9%) adalimumab. Of these, 53 (33%) started the biosimilar as their first biologic therapy. Fifty (31%) patients switched from their originator, median (IQR) time on originator before switch was 2.2 (1.1-4.1) years, with most citing cost or hospital policy (n = 22) as the reason and these patients had low disease activity (median active joint count was zero) at point of switch. Fifty-six (35%) patients switched to a biosimilar from a non-originator biologic with 37 (66%) switching for efficacy reasons and 13 (23%) for safety reasons, with higher disease activity reported (median active joint count was three); most (n = 32) switching from adalimumab. Follow-up data was available in 143 patients; median follow-up time was 1.1 (0.7, 1.9) years. Sixty-seven patients switched to another biologic in this period. The majority (n = 38) switched to a non-originator biologic, predominantly adalimumab (n = 22) or tocilizumab (n = 14). Nineteen patients switched between infliximab biosimilars. Ten patients switched to the originator biologic (two due to inefficacy, four due to adverse events, four due to painful injections), although only four of these were on the originator prior to starting biosimilar; overall, in patients who switched from originator to biosimilar, 8% switched back to the originator. Conclusion Biosimilars in children and young people with JIA are being used as both first-line and subsequent-line biologic therapy. Patients starting a biosimilar from an originator product had lower disease activity and reported switching due to cost reasons, whilst patient starting a biosimilar from a non-originator were doing so due to inefficacy. Overall tolerance of biosimilar appears to be good so far, with few patients switching back to the originator. It is imperative that these patients continue to be followed within the registers so that effectiveness and safety of these treatments can be captured. Conflicts of Interest The authors declare no conflicts of interest.

Background Composite disease scores in juvenile idiopathic arthritis (JIA), such as the clinical Juvenile Arthritis Disease Activity Score (cJADAS), include multiple disease manifestations, presented as a single score. These overall scores aid understanding of disease holistically in each child or young person (CYP), and have been suggested as outcomes for clinical trials and targets in treat to target clinical strategies. However, signs and symptoms of disease may not follow similar patterns following a JIA diagnosis. It is not currently known what the patterns of disease activity are in CYP with JIA and how these cluster over time. Methods CYP with JIA were selected if enrolled in the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort, before January 2015. cJADAS10 components (active joint count 0-10, physician global, patient/parent global) were collected at diagnosis, six months, one year and then annually to three years. Multivariate group-based trajectory models modelled cJADAS10 component scores using censored-normal (physician and parent global) and zero-inflated Poisson (active joint count) distributions. Within linear, quadratic and cubic polynomials, one to ten trajectories were tested. The optimal models were selected using Bayesian Information Criteria, model parsimony and clinical plausibility. Results Of 1,183 CYP selected, the majority were female (65%) and of white ethnicity (90%) with oligoarticular JIA the most common JIA category (45%). The optimal model identified six multivariate patterns of disease. In four of these clusters, signs and symptoms of disease had similar patterns over time: Low-Remission (32%), Low-Low (20%), High-Low (16%) and High-Low-High (10%). However, in two groups, Low-Chronic (14%) and High Chronic (8%), manifestations of inflammation and wellbeing followed different trajectory severities and shapes over time. These groups demonstrated persistent poor wellbeing despite control of inflammatory signs. Conclusion Disease activity in CYP with JIA does not improve in a uniform manner following initial presentation to paediatric rheumatology. Six latent multivariate trajectories have been identified in young people with JIA, two of which persist with chronic poor wellbeing despite lowered inflammation. Conflicts of Interest The authors declare no conflicts of interest.

Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care.

Objective In order to develop interventions to optimize MTX use for the treatment of RA we evaluated the rate of, reasons for and predictors of MTX non-adherence during the first 6 months of therapy. Methods The Rheumatoid Arthritis Medication Study (RAMS) is a prospective multicentre cohort study of incident MTX users in the UK. Prior to MTX commencement demographic, clinical and psychological data were collected. A weekly patient-completed diary recorded MTX dose, possible side effects and adherence over 26 weeks. The number of non-adherent weeks was calculated. Potential baseline predictors of ever non-adherence (⩾1 week non-adherent) during the first 6 months of MTX therapy were identified using logistic regression analyses. Results 606 patients with RA were included; 69% female, mean (s.d.) age 60 (13) years and DAS28 score 4.2 (1.2). Over the first 6 months following MTX initiation, 158 (26%) patients were ever non-adherent (71% intentional, 19% non-intentional, 10% unexplained) and mean (s.d.) number of non-adherent weeks was 2.5 (2.1). Multivariable predictors of ever non-adherence included DAS28 [odds ratios (OR) 1.1, 95% CI 1.0, 1.4], fatigue (OR 1.1, 95% CI 1.0, 1.2 per cm), ⩾2 comorbidities vs no comorbidities (OR 1.9, 95% CI 1.1, 3.5) and high medication concerns despite perceived need (OR 1.1, 95% CI 1.0, 1.1 per unit decrease in need/concern differential). Conclusion This is the largest study evaluating early intentional and non-intentional non-adherence to MTX, which has identified that patient beliefs and multi-morbidity strongly link with non-adherence. These findings can direct the design of and provide potential targets for interventions to improve patient adherence.

ObjectivesPrevious ecological data suggest a decline in the need for joint replacements in RA patients following the introduction of TNF inhibitor (TNFi) therapy, although patient-level data are lacking. Our primary aim was to estimate the association between TNFi use and subsequent incidence of total hip replacement (THR) and total knee replacement.MethodsA propensity score matched cohort was analysed using the British Society for Rheumatology Biologics Registry (2001–2016) for RA data. Propensity score estimates were used to match TNFi users to similar conventional synthetic DMARD users (with replacement) using a 1:1 ratio. Weighted multivariable Cox regression was used to estimate the impact of TNFi on study outcomes. Effect modification by baseline age and disease severity were investigated. Joint replacement at other sites was also analysed. An instrumental variable sensitivity analysis was also performed.ResultsThe matched analysis contained a total of 19 116 patient records. Overall, there was no significant association between TNFi use vs conventional synthetic DMARD on rates of THR (hazard ratios = 0.86 [95% CI: 0.60, 1.22]) although there was significant effect modification by age (P < 0.001). TNFi was associated with a reduction in THR among those >60 years old (hazard ratio = 0.60 [CI: 0.41, 0.87]) but not in younger patients. No significant associations were found for total knee replacement or other joint replacement.ConclusionOverall, no association was found between the use of TNFi and subsequent incidence of joint replacement. However, TNFi was associated with a 40% relative reduction in THR rates among older patients.

The consequences of persistent active disease in juvenile idiopathic arthritis (JIA) include chronic pain and disability, in addition to growth disturbances and joint damage1,2. The last 2 decades have seen the development and licensing of biological therapies for JIA, revolutionizing patient care3. Now, more than ever, resolution of the signs and symptoms of JIA (i.e., remission) may be an attainable goal. However, even in cohorts of children and young people (CYP) with JIA where these newer therapies are widely available, fewer than 50% of CYP achieve remission in the first 10 years following diagnosis4. For outcomes to improve in JIA, clinicians must take advantage of the window of opportunity. This window represents a short time after diagnosis whereby early treatments may be most effective5. Thus, appropriate therapies must be used as early as possible. There is an ongoing push toward stratified or personalized medicine across specialties, including rheumatology6. If nonremission could be predicted, patients at higher risk could be managed differently, for example, with the earlier use of targeted therapies such as biologics. This would additionally minimize the risk of adverse events from exposure to unnecessary therapies that may be less successful at controlling disease in that patient. However, it is currently unclear which patients are predisposed toward a remission-like … Address correspondence to Prof. K.L. Hyrich, 2.800 Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK. E-mail: Kimme.hyrich{at}manchester.ac.uk

Background Joint erosions and autoantibody positivity (rheumatoid factor [RF], anti-cyclic citrullinated peptide antibody [anti-CCP]) predict poor outcomes in patients with rheumatoid arthritis (RA). There are limited data on the combination of these factors and clinical and patient reported outcomes over time. Objectives To compare the disease activity and disability over 1 year of those with poor prognostic factors at treatment initiation (methotrexate [MTX] or biologics) to those without. Methods Patients were recruited to 1 of 2 UK-based multi-centre prospective cohort studies: MTX-starters: Rheumatoid Arthritis Medication Study (RAMS); biologic-starters: Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Anti-CCP (Axis-Shield Anti-CCP test; U/ml; anti-CCP titre >5 U/ml = anti-CCP+)/RF (Beckman Coulter AU5400, RF latex assay; IU/ml; RF titre >14 IU/ml = RF+) status were determined from baseline (BL) blood samples at the co-ordinating centre; erosions (yes/no) were recorded from medical notes. Missing data resulting from anti-CCP assay failure were imputed using multiple imputation. Patients who were anti-CCP+ and/or RF+ and had erosions were classified as having poor prognosis (PP); all other patients were classified as not having poor prognosis (NPP). Patients completed the Health Assessment Questionnaire (HAQ) and the Disease Activity Score (DAS28) was calculated at BL, 6 months and 12 months. The DAS28 and HAQ scores of the prognostic groups were compared at each assessment using linear regression, adjusted for age, gender and disease duration. Results In total, 1179 (PP = 182 [15.4%]) MTX-starters and 1152 (PP = 467 [40.5%]) biologic-starters were included (BL characteristics in Table). For MTX-starters, PP and NPP patients had similar DAS28, whereas for biologic-starters, PP patients had lower DAS28 compared to NPP patients after baseline (adjusted mean difference [95% CI]: MTX-starters BL = 0.1 [-0.1, 0.3]; 6 months = -0.1 [-0.3, 0.2]; 12 months = -0.1 [-0.4, 0.2]; biologic-starters BL = -0.1 [-0.2, 0.0]; 6 months = -0.2 [-0.4, 0.0]; 12 months = -0.4 [-0.6, -0.1]). HAQ scores were similar between PP and NPP patients in both cohorts (adjusted mean difference [95% CI]: MTX-starters BL = 0.08 [-0.04, 0.20]; 6 months = 0.02 [-0.11, 0.15]; 12 months = -0.03 [-0.17, 0.10]; biologic-starters BL = 0.00 [-0.09, 0.08]; 6 months = 0.00 [-0.12, 0.13]; 12 months = 0.01 [-0.14, 0.16]). Conclusion PP and NPP MTX-starters had similar outcomes. For biologic-starters, PP patients had lower disease activity after baseline; knowledge of these prognostic factors may have prompted more intensive assessment of PP patients after starting treatment. Disclosure of Interests James Gwinnutt: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB, Mark Lunt: None declared, Darren Plant: None declared, Nisha Nair: None declared, Anne Barton: None declared, Suzanne Verstappen: None declared

Background: Tocilizumab (TCZ) is a biological disease-modifying antirheumatic drug that blocks IL-6 signalling and is effective in ameliorating disease activity in rheumatoid arthritis (RA). Despite this, approximately 50% of patients do not respond adequately to TCZ and some patients report adverse events. Considering there is growing evidence that DNA methylation is implicated in RA susceptibility and response to some biologics (1, 2), we investigated methylation patterns as a candidate biomarker for response to TCZ in RA. Objectives: To identify differential DNA methylation signatures in whole blood associated with TCZ response in patients with RA. Methods: Epigenome-wide DNA methylation patterns were measured using the Infinium EPIC BeadChip (Illumina) in whole blood-derived DNA samples from patients with RA. DNA was extracted from blood samples taken pre-treatment and following 3 months on therapy, and response was determined at 6 months using the Clinical Disease Activity Index (CDAI). Patients who had good response (n=10) or poor response (n=10) to TCZ by 6 months were selected. Samples from secondary poor responders (n=10) (patients who had an improvement of CDAI and were in remission at 3 months, followed by a worsening of CDAI at 6 months) were also analysed. Differentially methylated positions (DMPs) were identified using linear regression, adjusting for gender, age, cell composition, smoking status, and steroids use. Results: There were 20 DMPs significantly associated with response status at 6 months in the pre-treatment samples, and 21 DMPs associated with response in the 3 months samples (unadjusted P-value Conclusion: Whilst further analyses comparing sub-components of the CDAI with changes in methylation is ongoing, these preliminary results provide evidence that DNA methylation patterns may predict response to TCZ. Validation of these findings in other larger data sets is required. References: [1] Liu,Y., Aryee,M.J., Padyukov,L., Fallin,M.D., Hesselberg,E., Runarsson,A., Reinius,L., Acevedo,N., Taub,M., Ronninger,M., et al. (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol., 31, 142–147. [2] Plant,D., Webster,A., Nair,N., Oliver,J., Smith,S.L., Eyre,S., Hyrich,K.L., Wilson,A.G., Morgan,A.W., Isaacs,J.D., et al. (2016) Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. (Hoboken, N.J.), 68, 1353–60. Disclosure of Interests: Nisha Nair: None declared, Darren Plant: None declared, John Isaacs Grant/research support from: Pfizer, Grant/research support from: Pfizer, Consultant for: Abbvie, Pfizer, Roche, Galvani, Merck, Gilead, Eli Lilly, Amgen, Janssen, Celltrion, NAPP, Consultant for: Abbvie, Pfizer, Roche, Galvani, Merck, Gilead, Eli Lilly, Amgen, Janssen, Celltrion, NAPP, Speakers bureau: Abbvie, Pfizer, Eli Lilly, Speakers bureau: Abbvie, Pfizer, Eli Lilly, Ann Morgan: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB, Anne Barton: None declared, Gerry Wilson: None declared

Background: Whilst anti-cyclic citrullinated peptide antibody (anti-CCP) positivity in associated with poor outcomes in patients with rheumatoid arthritis (RA), it is unclear whether titre level over time is associated with outcome. Objectives: Whilst anti-cyclic citrullinated peptide antibody (anti-CCP) positivity in associated with poor outcomes in patients with rheumatoid arthritis (RA), it is unclear whether titre level over time is associated with outcome. Methods: Patients were recruited to one of two, UK-based, multi-centre prospective cohort studies: MTX-starters = Rheumatoid Arthritis Medication Study (RAMS); biologic-starters = Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). Anti-CCP titre (Axis-Shield Anti-CCP test; U/ml; anti-CCP titre >5 U/ml = anti-CCP+) was measured at the co-ordinating centre from blood samples taken at baseline, 6 months and 12 months. Patients who were anti-CCP+ at baseline and had titre measured at one other assessment were included in the analysis. Patients completed the Health Assessment Questionnaire (HAQ) and the Disease Activity Score (DAS28) was calculated at each assessment. The association between anti-CCP titre and DAS28 and HAQ was assessed using linear random effects models, controlling for age, gender and disease duration (months). Anti-CCP titre was natural log-transformed. Missing data resulting from anti-CCP assay failure were imputed using multiple imputation. Results: In total, 686 MTX-starters and 346 biologic-starters were included. Biologic-starters had worse disease at baseline compared to MTX-starter (Table). Median [IQR] titre decreased slightly over follow-up for MTX-starters (baseline = 147 [48, 416]; 6 months = 133 [47, 454]; 12 months = 124 [44, 421]; p=0.63) and biologic-starters (baseline = 138 [37, 492]; 6 months = 112 [30, 468]; 12 months = 103 [30, 451]; p=0.36) but this was non-significant. For MTX-starters, anti-CCP titre was statistically significantly associated with DAS28 and HAQ, but the effect sizes were small (mean difference [95% CI] per unit increase in log anti-CCP: DAS28 = 0.07 [0.02, 0.11]; HAQ = 0.06 [0.03, 0.08]). There was no significant association between anti-CCP titre and DAS28 and HAQ for biologic-starters (mean difference [95% CI] per unit increase in log anti-CCP: DAS28 = 0.03 [-0.05, 0.10]; HAQ = 0.02 [-0.01, 0.05]). Conclusion: Time-varying anti-CCP titre level was not strongly associated with disease activity or disability over one year in either MTX-starters or biologic-starters who were anti-CCP+ at baseline, indicating repeat testing of anti-CCP level may not be necessary. Disclosure of Interests: James Gwinnutt: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB, Mark Lunt: None declared, Darren Plant: None declared, Nisha Nair: None declared, Anne Barton: None declared, Suzanne Verstappen: None declared

Background: Biologic therapies, second-line treatment after failure of methotrexate, have revolutionised treatment pathways and outcomes for patients with juvenile idiopathic arthritis (JIA). The expanding choice allows patients to switch biologic if current treatment is not working. Current NHS England guidelines recommend most patients with JIA to start a tumour necrosis factor inhibitor (TNFi), and if that fails switch to a second TNFi rather than change class. The evidence base for this in JIA is limited. Objectives: The aim of this study was to compare the effectiveness of a second TNFi versus an alternative class of biologic therapy in patients with polyarticular JIA following initial TNFi therapy in routine clinical practice. Methods: Analysis included patients with JIA starting a second biologic following initial TNFi therapy in two UK cohort studies; BSPAR-ETN and BCRD. Within the studies, data were collected at start of biologic, 6 months, 1 year, then annually on patient characteristics and anti-rheumatic therapy. Patients with extended oligoarticular and polyarticular (rheumatoid factor positive and negative) JIA were included. Patients with a history of uveitis at start of second biologic were excluded. Patient characteristics at start of second biologic were compared between patients starting a second TNFi versus an alternative class. Kaplan-Meier drug survival was used to assess drug survival on second biologic. Stop reasons of second biologic were described. Change in core outcome variables, JADAS-71, American College of Rheumatology Paediatric 50% response (ACR Pedi 50), and Minimal Clinically Important Difference (MCID; ≤0.13 reduction in CHAQ) from baseline to one year was compared between the two cohorts. Multiple imputation and propensity scores were used to account for missing baseline co-variate data and adjust for confounding by indication. Results: 151 patients with polyarticular JIA starting a second biologic up to 13-Nov-2018 were included; 115 (76%) a second TNFi, 36 (24%) an alternative class. Patient characteristics at the start of second biologic were mostly similar except patients starting a non-TNFi had lower CRP levels (p Conclusion: In this real-world cohort of children and young people with JIA starting a second biologic following initial TNFi therapy failure, there appears to be no difference between drug survival and effectiveness outcomes in those patients switching to a second TNFi compared with a non-TNFi biologic. Further research on larger sample sizes is required to know whether there is any initial advantage to switching class of drug following failure of a first TNFi. Disclosure of Interests: Lianne Kearsley-Fleet: None declared, Rebecca Davies: None declared, Jennifer Page: None declared, Eileen Baildam: None declared, Michael Beresford: None declared, Helen Foster: None declared, Taunton Southwood: None declared, Wendy Thomson: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB

Background: In 2017 a new class of oral disease modifying anti-rheumatic drugs (DMARDs), janus kinase inhibitors (JAKi), were licensed for rheumatoid arthritis (RA): baricitinib and tofacitinib. In the UK, they are approved for use in patients with high disease activity with or without methotrexate, following failure of conventional synthetic (cs) DMARDs or biologic DMARDs, the latter when rituximab is contraindicated. As a new therapy option, it is currently unclear how and when these drugs are being prescribed in patients with RA. Objectives: This analysis aims to describe the characteristics of patients starting JAKi and registered with the BSRBR-RA. Methods: The BSRBR-RA aims to capture exposure and outcome data in patients with RA receiving biologics, biosimilars and targeted synthetic DMARDs. At the start of therapy, demographic and clinical data, including past treatment data, are collected. Characteristics of all patients receiving a JAKi for the first time with data recorded in the BSRBR-RA up to 30/11/2018 are described. Results: To 30/11/2018, 443 patients in the BSRBR-RA have been treated with a JAKi; 374 patients baricitinib and 69 tofacitinib (Table). Twenty-eight percent of baricitinib and 13% of tofacitinib patients received a JAKi following csDMARDs, with no prior biologic exposure. Of these, 15% had a prior malignancy history. Of those with prior exposure, the median number of previous biologics was 3 (IQR 2-4) and 52% had received rituximab. Forty-three percent were receiving concurrent methotrexate. Conclusion: To date, more patients have been recruited starting baricitinib than tofacitinib, likely owing to the later licensing of tofacitinib. Two groups are emerging with a quarter of patients receiving JAKi immediately after csDMARDs and a majority as a later stage alternative following multiple biologics. Further recruitment and follow-up patients will allow for analysis of real-world safety and effectiveness, but differences in patient characteristics will need to be considered in any comparative effectiveness analyses. Disclosure of Interests: Jennifer Page: None declared, Lianne Kearsley-Fleet: None declared, Rebecca Davies: None declared, Kath Watson: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB, Mark Lunt: None declared

Background: Since February 2015, a number of biosimilar drugs have been introduced for treatment of rheumatoid arthritis (RA) in the UK. Biosimilars are required to have no clinically meaningful differences in efficacy or safety from the originator product. There are clear cost-saving implications when switching patients to a biosimilar; however, the longer term implications of switching have yet to be studied. Objectives: To describe the frequency of switching back to biologic-originator (BIO-O) in patients who initially switch from BIO-O to biologic biosimilar (BIO-B), focussing on etanercept (ETA) and infliximab (INF). Methods: The study population comprised RA subjects recruited to BSRBR-RA to 30/11/2018 who had switched from BIO-O to BIO-B (INF and ETA) and had completed at least one further study follow-up following switch. Baseline characteristics at point of switch and the proportion of patients who were recorded as switching back to BIO-O or discontinuing BIO completely following switch with reasons are described. Results: Nine hundred and sixty six patients were included (760 switching from ETA-O; 206 switching from INF-O). After a median follow-up of 22.5 months post-switch, the majority of patients remained on BIO-B (ETA-B = 619 (81%), INF-B =166 (81%)). Seven percent of patients switched back to originator, with a majority following reports of ineffectiveness or feeling generally unwell (Table). Eleven percent stopped BIO completely, with a majority stopping for serious adverse events such as malignancy or infection. Similar results were seen for both ETA and INF. Six ETA and 3 INF reported injection or infusion related reactions following switch (0.9% overall) leading to switch back (4 ETA) or biologic discontinuation (2 ETA/3 INF). Conclusion: Data from this study show that the majority of patients who switched from BIO-O to BIO-B remain on the biosimilar over the short term. A small proportion of patients have switched back to the originator drug with the majority doing so for reports of ineffectiveness rather than safety concerns. Hypersensitivity reactions, such as infusion reactions were rare reasons to stop either drug completely or switch back to originator. Disclosure of Interests: Rebecca Davies: None declared, Lianne Kearsley-Fleet: None declared, Mark Lunt: None declared, Kath Watson: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB