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ObjectivesTo perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).MethodsSLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.ResultsFifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9–2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.ConclusionThe safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.

Introduction/Background Juvenile idiopathic arthritis (JIA) encompasses a group of heterogeneous rheumatic diseases of childhood onset. JIA can result in long term disability and remission is the main goal of treatment. However refractory disease can occur, which is defined as the absence of response to a standard disease therapy. A genetic basis for refractory disease has yet to explored, where deleterious rare variants complicate diagnosis or treatment outcome. This study aimed to investigate, through genetic analysis, whether children with JIA that is refractory carry rare genetic risk factors in genes linked to monogenic diseases. Description/Method Whole exome sequencing of 99 children with JIA was performed with the Agilent SureSelect Human All ExonV6 kit. All quality control, variant filtering and annotation was performed in Varseq (version 2.2.1). Variants with a read depth 1% (based on ExAC, gnomAD, gnomAD exome, NHLBI and 1KGp phase 3), classified as benign or likely benign on ClinVar, with a CADD PHRED score 0.7. Variants were annotated if they appeared in a gene from the primary immunodeficiency PanelApp (Martin et al., 2019), in a gene associated with an arthritis phenotype or in a gene that appeared on a paediatric monogenic gene list. The variants were then classified using ACMG guidelines (Richards et al., 2015) and benign, or likely benign, classified variants were removed. Discussion/Results A total of 470 variants were identified and we found that 20 out of the 99 children screened were heterozygous for at least one recognised variant in a gene linked to a monogenic disease. Five of these children carried more than one recognised variant linked to monogenic genes. Here we provide a number of illustrative examples: three genes, ADAR, ATP7B and MVK, were prioritised based on prior evidence of associated disease. The variant p.Pro193Ala (gnomAD allele frequency (GAD) 2.2x10-3) of ADAR has previously been deemed pathogenic in a homozygous or compound heterozygous state for Aicardi-Goutières syndrome. Adenosine deaminases (ADARs) catalyse the hydrolytic deamination of adenosine to inosine in dsRNA and is suggested to act as a suppressor of type 1 interferon-stimulated genes. Within ATP7B, two distinct variants were detected; p.Gln1142His (GAD 1.6x10-5) and p.Ile1148Thr (GAD 4.0x10-5) have previously been reported as pathogenic, in combination with a third variant, for Wilson’s disease and were carried by one individual in this cohort. ATP7B encodes copper-transporting ATPase 2, which supplies copper to ceruloplasmin. Variant p.Val377Ile (GAD 1.6x10-3) of MVK was detected in eight individuals in this cohort, interestingly five of these individuals also carried at least one HLA-DRB1 stop-gained variant. This MVK mutation has been confirmed as pathogenic in a homozygous or compound heterozygous state for mevalonate kinase deficiency. MVK converts mevalonic acid into mevalonate-5-phosphate in the cholesterol synthesis pathway. Additionally, two stop-gained loss of function HLA-DRB1 variants, p.Tyr107Ter and p.Gln125Ter, were detected in five and 20 individuals, respectively, in this cohort. HLA-DRB1 is a recognised susceptibility locus for JIA. Key learning points/Conclusion Screening of a cohort of 99 children with JIA that have refractory disease has revealed that individuals carry deleterious variants in genes linked to monogenic forms of disease. These results highlight that the genetic basis for refractory disease needs to be further investigated. Carrying additional genetic risk factors to disease may complicate disease outcome and genetic screening of children with refractory JIA may improve treatment outcome in the future.

Introduction/Background There is a lack of data on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs) as they were excluded from initial vaccine trials. Vaccination guidance is based on data from adults with or CYP without RMDs. Description/Method Our objective was to describe the safety of SARS-COV-2 vaccination in adolescents with inflammatory RMDs and adults with JIA. We described patient characteristics, flares, and adverse events in adolescent cases under 18 with inflammatory RMDs and adult cases aged 18 or above with JIA submitted to the European Alliance of Associations for Rheumatology (EULAR) COVAX registry. Discussion/Results Thirty-six adolescent cases were reported from 4 countries, mostly female (58%) with JIA (42%: 28% non-systemic JIA, 14% systemic JIA) and a median age of 15 [IQR: 14.5, 17]. Most were in remission (64%) or had minimal (22%) disease activity at the time of vaccination. Over half of the adolescent group (56%) reported early reactogenic-like AEs. One mild polyarthralgia flare and one serious AE of special interest (malaise) were reported. No CYP reported SARS-CoV-2 infection post-vaccination. No cases of paediatric inflammatory multi-system syndrome or myocarditis adverse events were reported. Seventy-four adult JIA cases were reported from 11 countries; 73% were female with a median age of 26 [IQR: 23, 31]. Eight-five percent had ns-JIA and 15% had s-JIA. Almost two thirds (62%) reported early reactogenic-like AEs and two flares were reported (mild polyarthralgia and moderate uveitis). No serious AEs of special interest were reported among adults with JIA. Three 20-30 year old females were diagnosed with SARS-CoV-2 post-vaccination; all fully recovered. Key learning points/Conclusion In this observational registry dataset, SARS-CoV-2 vaccines appeared safe in adolescents with RMDs and adults with JIA, with a low frequency of disease flares, serious AEs, and SARS-CoV-2 re-infection seen in both populations.

Introduction/Background It is estimated that juvenile idiopathic arthritis (JIA) persists into adulthood in at least one-third of patients, but it is unclear how frequently hospital services are used as young people move from paediatric to adult specialist services. This study aimed to describe characteristics related to continued specialist care in young people (YP) with JIA using electronic health records (EHR) in England. Description/Method YP with JIA were identified from primary care EHR (Clinical Practice Research Datalink GOLD and Aurum databases combined) between 2003 and 2018. JIA was identified if they had a Read code for JIA and either > =3 Hospital Episode Statistics (HES) outpatient specialist care (rheumatology/ophthalmology) appointments or a HES inpatient admission coded with JIA, prior to age 16. Further, cases needed to have linkage to HES data, registration at the same GP for >1 year beyond age 18. Cases were followed from the earliest of first Read code or first HES outpatient appointment until leaving their GP or end of 2018. Continuity of specialist care was categorised into 3 groups by age of last specialist care appointment: prior to 16 years, 16 to 17 years, and 18 years and beyond. YP were considered discharged from specialist care (a proxy for disease remission) if they had > =1 year between the last appointment and end of study follow-up. Multinomial logistic regression model assessed if any demographic or comorbidity variables were associated with continuing specialist care category. Discussion/Results Of 666 YP eligible, 427 (64%) received specialist care beyond age 18, 90 (13%) had their last recorded contact between 16-17 years and 149 (22%) did not continue after 16 years. Patients characteristics are described in Table 1. Of those continuing beyond 18, 35% (n = 153) were subsequently discharged by study end date. Of all those discharged, 32% had a missed appointment recorded after the last visit attended suggesting failure to attend. In the regression model, female gender and a childhood diagnosis of uveitis were associated with continuing specialist care beyond age 18 compared to those discharged before age 16; respective adjusted odds ratio (95% confidence intervals) 1.84 (1.25, 2.72) and 2.23 (1.14, 4.35). Key learning points/Conclusion Over two-third of patients with JIA continue to have hospital visits beyond age 18. Of those, however, approximately one-third were subsequently discharged or lost to follow up from adult specialist care. These data provide important information for YP with JIA and their families, as well as clinicians running, developing and planning young adult services in paediatric and adult rheumatology.

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

Introduction/Background Oligoarthritis, a sub-type of JIA, can be categorised as persistent or extended. Children with persistent oligoarthritis, involving Description/Method This aim of this research is to conduct a systematic literature review on the clinical and patient-reported outcomes of persistent oligoarthritis. This abstract presents plans and current status of the review. Inclusion criteria for this systematic review are 1) inception cohorts with at least partial prospective data collection, 2) available in English language, 3) includes at least 50 patients with persistent oligoarthritis using ILAR criteria, 4) investigates clinical or patient-reported outcome. Exclusion criteria are 1) not specifically presenting or analysing outcomes in persistent oligoarthritis and 2) not reporting disease duration or follow-up time points from diagnosis at the point of outcome measurements. Search terms related to ‘oligoarthritis’, (variants of juvenile oligoarthritis plus outcomes of interest) were used in MEDLINE and Embase from 01/01/1997 to 30/05/2022 to cover the advent of current ILAR categories to present. These terms were also entered into PubMed from 30/05/2020 to 30/05/2022 to include publications published online ahead of print. Quality assessment, including common biases, of selected articles will be assessed using relevant questions from the Pasma et al. quality assessment (QA) tool. Primary outcomes are the core JIA outcome variables (active joint counts, limited joint count, physician’s global assessment, parent global evaluation, erythrocyte sedimentation rate and additional functional status (CHAQ/HAQ). Additional outcomes are 1) remission status, 2) uveitis status, 3) pain, 4) Health-related Quality of Life and 5) treatment response. One reviewer will initially screen titles and abstracts. Two reviewers will then screen the full text of selected articles independently and agree the master list. The first reviewer will then extract data regarding study populations and outcome and another reviewer will check a selection of the extracted data. If there is disagreement or uncertainty between the two reviewers at any stage, a third reviewer will adjudicate. Discussion/Results To date 1051 publications have been highlighted for initial review (title and abstract) by the first reviewer. The second review is now underway by the two reviewers and preliminary results will be ready to present soon. The review has been registered with Prospero (ID: CRD42022291943). Key learning points/Conclusion There is an unmet need for improved understanding of outcome in persistent oligoarthritis. This systematic review will help inform treatment targets and future research in this common ILAR JIA category.

Objective To describe obstetric outcomes based on COVID-19 vaccination status, in women with rheumatic and musculoskeletal diseases (RMDs) who developed COVID-19 during pregnancy. Methods Data regarding pregnant women entered into the COVID-19 Global Rheumatology Alliance registry from 24 March 2020–25 February 2022 were analysed. Obstetric outcomes were stratified by number of COVID-19 vaccine doses received prior to COVID-19 infection in pregnancy. Descriptive differences between groups were tested using the chi-squared or Fisher’s exact test. Results There were 73 pregnancies in 73 women with RMD and COVID-19. Overall, 24.7% (18) of pregnancies were ongoing, while of the 55 completed pregnancies, 90.9% (50) of pregnancies resulted in livebirths. At the time of COVID-19 diagnosis, 60.3% (n = 44) of women were unvaccinated, 4.1% (n = 3) had received one vaccine dose while 35.6% (n = 26) had two or more doses. Although 83.6% (n = 61) of women required no treatment for COVID-19, 20.5% (n = 15) required hospital admission. COVID-19 resulted in delivery in 6.8% (n = 3) of unvaccinated women and 3.8% (n = 1) of fully vaccinated women. There was a greater number of preterm births (PTB) in unvaccinated women compared with fully vaccinated 29.5% (n = 13) vs 18.2% (n = 2). Conclusions In this descriptive study, unvaccinated pregnant women with RMD and COVID-19 had a greater number of PTB compared with those fully vaccinated against COVID-19. Additionally, the need for COVID-19 pharmacological treatment was uncommon in pregnant women with RMD regardless of vaccination status. These results support active promotion of COVID-19 vaccination in women with RMD who are pregnant or planning a pregnancy.

Background/Aims Tumour necrosis factor inhibitors (TNFi) have advanced the clinical management of rheumatoid arthritis (RA); however, only 30-40% of patients who receive initial treatment with a TNFi experience a beneficial response. The discovery of biomarkers of TNFi response would facilitate improved response rates and more objective monitoring of inflammation. Gene transcript levels measured in the blood of RA patients represent an attractive source of biomarkers. For example, a study by Oswald et al demonstrated reproducible changes in gene expression modules in RA patients treated effectively with a TNFi. Such gene modules were previously defined by Chaussabel et al following the assessment of gene co-expression patterns, transcript clustering patterns and functional associations amongst transcripts from several inflammatory diseases. We aim to replicate the changes in modular gene co-expression reported to occur in response to TNFi therapy in RA in a UK cohort described by Oswald et al; to test if changes in modular expression are specific to TNFi therapy by analysing change in gene co-expression in response to methotrexate (MTX); and to determine if module expression transitions towards a disease-free state in responding patients. Methods Published whole blood transcriptomic data from disease-free controls (n = 10) and RA patients treated with either the TNFi adalimumab (n = 70) or MTX (n = 85) were studied. Transcriptomic data were available at pre-treatment and at 3-months (TNFi) and 4-weeks (MTX) post-treatment. Response to treatment was assessed using the EULAR response criteria following 3/6-months on-drug. For each of the 27 modules, the fraction of probes that significantly (p < 0.05) changed in expression between time-points was recorded. Linear mixed models were used to test if module expression transitioned towards a disease-free state following treatment. Results In the TNFi cohort, 25 of the 27 modules significantly changed in expression between pre- and post-treatment, replicating published findings by Oswald et al. Six of these 27 modules transitioned towards a disease-free state by 3-months. Transition in module expression was irrespective of treatment response in 5 of the 6 modules, however one module (module 3.2) appeared to be dependent on good response to adalimumab. This module was linked to pathways of inflammation and TNF signalling. Similar patterns of modular expression changes were observed in the MTX cohort, but with reduced significance compared to TNFi treated patients. Conclusion This study provides independent replication of changes in modular gene expression in TNFi treated RA patients. Gene expression changes were observed regardless of treatment response and were not specific to TNFi therapy. These results suggest that some factors of biological response are not detected by clinical classifiers of treatment response. Further research is now needed to test the utility of gene modules for prediction of clinical response, or for objective monitoring of molecular pathways that are responsive to treatment. Disclosure M.A. Sutcliffe: None. N. Nair: None. J. Oliver: None. A. Morgan: None. J. Isaacs: None. G. Wilson: None. S. Verstappen: None. S. Viatte: None. K. Hyrich: None. A. Morris: None. A. Barton: None. D. Plant: None.

Background/Aims It is estimated that juvenile idiopathic arthritis (JIA) persists into adulthood in at least one-third of patients, but it is unclear how frequently hospital services are used beyond age 16. This study aimed to describe characteristics related to continued specialist care in young people (YP) with JIA using electronic health records (EHR) in England. Methods YP with JIA were identified from primary care EHR (Clinical Practice Research Datalink GOLD and Aurum databases combined) between 2003 and 2018. JIA was identified if they had a Read code for JIA and either > =3 Hospital Episode Statistics (HES) outpatient specialist care (rheumatology/ophthalmology) appointments or a HES inpatient admission coded with JIA, prior to age 16. Further, cases needed to have linkage to HES data, registration at the same GP for >1 year beyond age 16. Cases were followed from the earliest of first Read code or first HES outpatient appointment until leaving their GP or end of 2018. YP with > =1 specialist care outpatient appointment beyond age 16 were identified. YP were considered discharged from specialist care (a proxy for disease remission) if they had > =1 year between the last appointment and end of study follow-up. Patient characteristics and characteristics of discharged are presented, stratified by continued specialist care. Results Of 1095 YP eligible for the study, followed for a median of 12 years beyond 16, 774 (70.7%) continued specialist care beyond age 16. These patients were older at first JIA code and more likely to be female (Table 1). Overall, 543 (51.9%) continued in specialist care beyond age 18. The median age of the last visit was 14 for those not continuing specialist care and 18 for those discharged after the age of 16. Disease duration was longer in those discharged after age 16. Conclusion Over two-third of patients with JIA continue to have hospital visits beyond age 16. Of those, however, approximately one-third were discharged from specialist care by the age of 18. These data provide important information for YP with JIA and their families, as well as clinicians running, developing and planning young adult services in paediatric and adult rheumatology. Disclosure R.E. Costello: None. L. Kearsley-Fleet: None. J.E. McDonagh: None. K. Hyrich: None. J.H. Humphreys: None.

Background/Aims Methotrexate (MTX) is the preferred first line therapy for rheumatoid arthritis (RA), according to NICE guidelines. MTX has several advantages over other treatments including effectiveness and low cost; however, around 40% of patients are classed as non-responders after 6 months. Therefore, there is a clinical need to identify patients at high-risk of poor outcomes, such that patients could potentially be fast tracked onto alternative therapies to improve their clinical outcomes and quality of life. Such risk stratification is possible through prognostic prediction models, although models which have previously been developed appear to have had little impact on practice. This may be in part due to methodological features of their development and validation but, to date, no review has collated the evidence in this field. This review therefore aimed to (i) identify and summarise multivariable prediction models of MTX treatment outcomes in biologic-naïve adult RA patients, and (ii) appraise their methodological properties. Methods A systematic search was carried out using Medline Ovid to identify studies developing or validating prediction models of MTX outcomes in the population of interest, including demographic, disease-specific or treatment-related covariates, published between 2005 and 2020. Models were stratified by outcome definition, and information on predictors, predictor associations with the outcome, model performance, handling of missing data and model validation were extracted. Results Twenty-two studies (14 (64%) using data from observational studies and 8 (36%) from randomised controlled trials) were identified. Of these, 15 (68%) based their outcome on a state of disease activity, such as low disease activity or remission, 4 (18%) used the EULAR response criteria, and 3 (14%) predicted discontinuation due to adverse events (AEs). AEs were also incorporated into the composite outcome with disease activity in 3 (14%) studies, 1 (5%) investigated both outcomes in separate models, and only 1 (5%) accounted for potential competing risks to their primary outcome. Internal validation using cross sampling techniques, which is critical for reducing overfitting, was completed in only 5 (23%) studies. Only 4 (18%) studies carried out external validation in new data. Missing data was appropriately handled using multiple imputation in 5 (23%) studies, whilst others used single imputation (n = 1, 4%) or complete case analysis (n = 13, 59%), resulting in potentially biased risk estimates, or did not report how they handled missing data (n = 3, 14%). Conclusion This review summarises current prediction models of MTX treatment outcomes in RA. It highlights several methodological shortcomings that should be addressed in future model development and validation to improve accuracy of predictions. Without tackling these issues, prediction of MTX treatment outcomes will remain at high risk of bias and should not be recommended for informing risk stratification for RA treatment decisions. Disclosure C. Gehringer: None. G. Martin: None. K. Hyrich: None. S. Verstappen: None. J. Sergeant: None.

Background/Aims Current British Society for Rheumatology guidance suggests 3-monthly blood monitoring for patients prescribed methotrexate whose disease, drug dosage and blood results are stable, although evidence for this recommendation is limited. Anecdotal reports suggest monitoring may have reduced during the pandemic. The study aims were, in patients with rheumatoid arthritis (RA) prescribed methotrexate, to determine: 1) interval length between blood tests during the pandemic, and 2) whether prolonged intervals were associated with abnormal blood test results. Methods Data came from the Greater Manchester Care Record, a database containing electronic health records from both primary and secondary care for people across Greater Manchester. Inclusion criteria were: a diagnosis of RA; regular blood monitoring ( < =91 days between blood tests) and regular methotrexate prescriptions in the year prior to the pandemic (01/03/2019-01/03/2020). Blood test intervals during the pandemic were determined, a prolonged interval was defined as > 91 days. Cytopenia and transaminitis events were identified between March-December 2020 and March-December 2019 (as a comparator). Proportions of events are presented for each time-period and stratified by whether the interval was prolonged. Results 1011 patients met the inclusion criteria, with a median of 5 blood tests (interquartile range (IQR): 3-7) during the pandemic and a median interval of 57 days (IQR: 34-84). 612 (61%) patients had at least one prolonged interval, with 241 (23.8%) having multiple. Prolonged intervals had a median length of 112 days (IQR: 99-135). 115 (11.4%) people had a prolonged interval but no subsequent blood test before the study end date (median 120 days [IQR: 104-150]). The proportion of cytopenia and transaminitis events was low and similar across time-periods and when stratified by interval length (Table 1). Conclusion Nearly two-thirds of patients on stable methotrexate had at least one prolonged interval and 1 in 10 had a prolonged interval with no subsequent blood test. Initial analyses of test results do not indicate increased occurrence of methotrexate blood toxicity in those with prolonged blood test intervals during the pandemic. Further work is required to determine whether those with prolonged intervals represent a group at lower risk where less frequent blood tests would be appropriate. Disclosure R.E. Costello: None. R. Williams: None. I.N. Bruce: None. K. Hyrich: None. W.G. Dixon: Consultancies; Consultancy fees from Abbvie and Google unrelated to this work. J.H. Humphreys: None.

Background/Aims Limited therapeutic efficacy and ‘difficult to treat’ (D2T) characteristics mean some rheumatoid arthritis (RA) patients cycle through multiple therapies to achieve their treatment targets. The aim of this study was to evaluate for subgroups of refractory RA (RefRA) in a real-world population and describe D2T characteristics. Methods Patients on their third or more targeted therapy were identified from the electronic health record (EHR) at Manchester Royal Infirmary. Demographic and clinic information were obtained. Raised disease activity was identified as DAS28ESR>3.2. Findings of power Doppler joint synovitis on ultrasound (PDUS) if undertaken within a month of clinical assessment. These data were used to categorise patients as raised disease activity and PD positive (persistent inflammatory RefRA, PIRRA) or raised disease activity in the absence of PD (non-inflammatory RefRA, NIRRA). Descriptive analyses were used to describe the characteristics in the two groups. Missing data were counted as negative observations. Results 82 patients who were on a third advanced therapy or higher were identified. 41/82 (50%) had raised disease activity and 32/41 (78%) had MSUS performed. 18/32 (56%) of these were PIRRA and 14/32 (44%) were NIRRA. Table 1 details demographic and clinical characteristics in the two groups as well as the controlled RefRA population. The PIRRA group had more erosive disease [13/18 (72%) PIRRA vs 8/14 (57%) NIRRA] and smoking history [9/18 (50%) of PIRRA vs 5/14 (35%) of NIRRA]. The PIRRA group also had greater levels of co-morbidity but previous bDMARD toxicity was comparable between the two groups. Whilst the DAS28ESR was higher in the PIRRA group, there were only marginal differences in the tender and swollen joint counts and CRP compared to NIRRA. The controlled RefRA population as expected showed notably lower DAS28-ESR and individual components although more similar to the PIRRA group with regards to comorbidity. Conclusion Just over half of the ref-RA cohort with raised disease activity had MSUS-detected synovitis and may be regarded as PIRRA. The PIRRA group had higher disease activity although joint counts and even acute phase were comparable. Higher smoking history and comorbidity appear to distinguish PIRRA and NIRRA in this cohort. Disclosure G. Rogers: None. Y. Tan: None. R. Shukla: None. R. Gorodkin: None. B. Parker: None. I. Bruce: None. J. Humphreys: None. A. Barton: None. K. Hyrich: None. E. Bruce: None. P. Ho: None. M.H. Buch: None.

Background/Aims The treatment of rheumatoid arthritis (RA) has improved since the introduction of targeted biological disease-modifying antirheumatic drugs (bDMARDs), such as adalimumab. However, no treatment options for RA are universally effective. Psychological factors may have an important role in treatment response. Published data reported that pre-treatment psychological variables such as an increased treatment necessity belief correlated with better adherence to adalimumab in RA patients. This current study aimed to investigate whether psychological factors correlate with change in 4V-DAS28-CRP as well as subcomponents of the score in adalimumab-treated RA patients. Methods Psychological, clinical and demographic data and DAS28 scores were collected pre-treatment, and at 3,6, and 12-months post-treatment, as part of a prospective national study, BRAGGSS. Sixteen pre-treatment clinical and psychological variables were tested for association with treatment response at 3 and 12 months. Multiple linear regression models were analysed and a Bonferroni corrected p-value of < 0.003 was applied at each interval to assess significance. Results Data was available for 501 patients at 3 months follow up. Pre-treatment Beliefs about Medicine Questionnaire (BMQ) scores with regards to treatment necessity (P = 0.001), and two domains of the Illness Perception Questionnaire (IPQ), which were treatment belief and treatment control (P = 0.0001), correlated with the change in DAS28 by 3 months (Table 1). At 12 months, data were available for 362 patients. The treatment belief domain of the pre-treatment Illness Perception Questionnaire correlated with the change in tender joint count (P = 0.001) (Table 1). At 12 months no other sub-components correlated with the psychological variables. Conclusion Pre-treatment scores with regards to Illness Perception and Beliefs about Medicine correlated with 4V-DAS28-CRP response at 3 months. Of the subcomponents of DAS28, the psychological variables showed the highest correlation with tender joint count; as the tender joint count receives the highest weighting in the 4 variable DAS28 score, this may confound the assessment of treatment response. It will be necessary to undertake further analyses to assess the predictive value of these potentially modifiable psychological variables identified, but to also understand factors contributing to these psychological scores, such as the role of severe disease itself on psychological beliefs. Disclosure N. Raza: None. N. Nair: None. D. Plant: None. K. Hyrich: None. A.W. Morgan: None. J. Isaacs: None. A.G. Wilson: None. A. Barton: None.

Background/Aims People with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs) were excluded from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccine clinical development programmes; therefore, concerns regarding the safety and effectiveness of SARS-CoV-2 vaccines in this population still exist. Previous studies in people with I-RMDs were small albeit reassuring in terms of the incidence of I-RMD flares and adverse events. Our aim was to describe the safety of vaccines against SARS-CoV-2 in people with I-RMD. Methods Physician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5/Feb/2021 to 27/Jul/2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively. Results The study included 5121 participants from 30 countries, 90% with I-RMDs (n = 4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n = 517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), 42% biologic DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD). Conclusion The safety profiles of SARS-CoV-2 vaccines in patients with I-RMD were reassuring, and comparable to patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients, and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients. Disclosure P.M. Machado: None. S. Lawson-Tovey: None. A. Strangfeld: None. E. Mateus: None. K. Hyrich: None. L. Gossec: None. L. Carmona: None. A. Rodrigues: None. B. Raffeiner: None. C. Duarte: None. E. Hachulla: None. E. Veillard: None. E. Strakova: None. G.R. Burmester: None. G.K. Yardimci: None. J.A. Gómez-Puerta: None. J. Zepa: None. L. Kearsley-Fleet: None. L. Trefond: None. M.M. Cunha: None. M. Mosca: None. M. Cornalba: None. M. Soubrier: None. N. Roux: None. O. Brocq: None. P. Durez: None. R. Conway: None. T. Goulenok: None. J.W.J. Bijlsma: None. I. McInnes: None. X. Mariette: None.

Background/Aims Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition affecting children and young people (CYP) with onset Methods CYP Results There were 1649 cases and 4748 controls included in this study. Most cases (1048, 64%) were female with median (interquartile range (IQR)) age at first JIA code 8.49 (4.20-12.05) years. Amongst cases, males were older at first JIA code, median (IQR) 9.80 (6.09-12.68) years, compared to females 7.55 (3.45-11.70) years. In both cases and controls, the proportion of CYP was highest in the most deprived quintile (IMD 1), 375/1649 (22.7%) and 1108/4738 (23.4%) respectively, and proportions remained similar in the remaining quintiles. There was no association identified between IMD quintile and occurrence of JIA, the multivariable odds ratio (95% CI) comparing most and least deprived groups was 0.98 (0.83-1.17). However, amongst cases there was an association between older age at diagnosis and higher SES [ß(95%CI) 0.15 years (0.01-0.29)] such that CYP in the IMD 5 quintile (highest SES) were on average 8 months older at their first JIA code compared to CYP in IMD 1. Conclusion This study found CYP from higher socio-economic groups appeared to be diagnosed at an older age than those from the least deprived backgrounds. Factors such as later presentation to healthcare after disease onset, delays in referrals to specialist care, delays in diagnosis by specialist care or differences in population demographics across IMD quantiles may all contribute to the older age of diagnosis in high SES group. Further research is required to explore these factors. Disclosure Y. Tan: None. R. Costello: None. K. Hyrich: None. J. Humphreys: None.

Objectives To estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with RA starting MTX. Methods Data came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥18 years with physician diagnosed RA and symptom duration ≤2 years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at 6- and 12-month follow-up visits. The period prevalence rates of AEs are reported for 0–6 months, 6–12 months and 0–12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression. Results A total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematological AEs (5.6%). Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological) and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated glomerular filtration rate and alcohol consumption were associated with less reporting of haematological AEs. Conclusions AEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AE occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.

ObjectiveTo describe coronavirus disease 2019 (COVID-19) and pregnancy outcomes in patients with rheumatic disease who were pregnant at the time of infection.MethodsSince March 2020, the COVID-19 Global Rheumatology Alliance has collected cases of patients with rheumatic disease with COVID-19. We report details of pregnant women at the time of COVID-19 infection, including obstetric details separately ascertained from providers.ResultsWe report on 39 patients, including 22 with obstetric detail available. The mean and median age was 33 years, range 24–45 years. Rheumatic disease diagnoses included rheumatoid arthritis (n = 9), systemic lupus erythematosus (n = 9), psoriatic arthritis/other inflammatory arthritides (n = 8), and antiphospholipid syndrome (n = 6). Most had a term birth (16/22), with 3 preterm births, 1 termination, and 1 miscarriage; 1 woman had yet to deliver at the time of report. One-quarter (n = 10/39) of pregnant women were hospitalized following COVID-19 diagnosis. Two of 39 (5%) required supplemental oxygen (both hospitalized); no patients died. The majority did not receive specific medication treatment for their COVID-19 (n = 32/39, 82%), and 7 patients received some combination of antimalarials, colchicine, anti–interleukin 1β, azithromycin, glucocorticoids, and lopinavir/ritonavir.ConclusionWomen with rheumatic diseases who were pregnant at the time of COVID-19 had favorable outcomes. These data have limitations due to the small size and methodology; however, they provide cautious optimism for pregnancy outcomes for women with rheumatic disease particularly in comparison to the increased risk of poor outcomes that have been reported in other series of pregnant women with COVID-19.

Objective.To identify (1) whether tumor necrosis factor inhibitor (TNFi) drug levels/anti-drug antibodies (ADAb) are associated with treatment response and disability in patients with psoriatic arthritis (PsA); and (2) the factors associated with TNFi drug levels.Methods.Patients were recruited from a national multicenter prospective cohort with longitudinal serum samples and 28-joint count Disease Activity Scores (DAS28)/Health Assessment Questionnaire (HAQ) measurement over 12 months.Results.Adalimumab (ADA) drug levels were significantly associated with ΔDAS28 (β 0.055, 95% CI 0.011–0.099; p = 0.014) and inversely with HAQ over 12 months (β −0.022, 95% CI −0.043 to −0.00063). Factors significantly associated with ADA drug levels were ADAb levels and body mass index.Conclusion.Drug level testing in ADA-initiated PsA patients may be useful in determining treatment response/disability over 12 months.

Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

A high prevalence of comorbidity is observed in patients with rheumatoid arthritis (RA) and the presence and type of comorbidity has a significant impact on mortality and quality of life in RA. Comorbidity also has an impact on treatment decisions and recognizing and managing comorbidities is an important aspect in the care of patients with RA. Some comorbidities occur as a direct result of RA or the treatments used, while others can be unrelated but have an effect on treatment and outcomes. In this chapter we describe the burden of comorbidity and the prevalence, risk factors, and management of important comorbidities seen in RA.

Additional file 2: Additional Results. Title of data: Additional methods identified in the review. Description of data: Further details about methodology discussed within the review.

Approximately 30-40% of rheumatoid arthritis (RA) patients who are initially started on low-dose methotrexate (MTX) will not benefit from the treatment. To date, no reliable biomarkers of MTX inefficacy in RA have been identified. The aim of this study was to analyze whole blood samples from RA patients at 2 time points (pretreatment and 4 weeks following initiation of MTX), to identify gene expression biomarkers of the MTX response.RA patients who were about to commence treatment with MTX were selected from the Rheumatoid Arthritis Medication Study. Using European League Against Rheumatism (EULAR) response criteria, 42 patients were categorized as good responders and 43 as nonresponders at 6 months following the initation of MTX treatment. Data on whole blood transcript expression were generated, and supervised machine learning methods were used to predict a EULAR nonresponse. Models in which transcript levels were included were compared to models in which clinical covariates alone (e.g., baseline disease activity, sex) were included. Gene network and ontology analysis was also performed.Based on the ratio of transcript values (i.e., the difference in logTesting for changes in gene expression between pretreatment and 4 weeks post-treatment initiation may provide an early classifier of the MTX treatment response in RA patients who are unlikely to benefit from MTX over 6 months. Such patients should, therefore, have their treatment escalated more rapidly, which would thus potentially impact treatment pathways. These findings emphasize the importance of a role for early treatment biomarker monitoring in RA patients started on MTX.

Table S1. Univariable and multivariable analysis of predictors of MTX non-response for those with active disease at baseline. Table S2. Univariable and multivariable analysis of predictors of failure to achieve low disease activity at 6Â months. Figure S1. Calibration plot for multivariable prediction model for non-response to MTX for those not in remission at baseline. Figure S2. Calibration plot for multivariable prediction model for non-response to MTX for those with active disease at baseline. Figure S3. Calibration plot for multivariable prediction model for failure to achieve low disease activity. (DOCX 60 kb)

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10

Objectives To determine if depressive symptoms assessed near diagnosis associate with future measures of pain, disability and disease for adolescent patients diagnosed with JIA. Methods Data were analysed from JIA patients aged 11–16 years recruited to the Childhood Arthritis Prospective Study, a UK-based inception cohort of childhood-onset arthritis. Depressive symptoms (using the Mood and Feelings Questionnaire; MFQ), active and limited joint count, disability score (Childhood Health Assessment Questionnaire), pain visual analogue scale and patient’s general evaluation visual analogue scale were collected. Associations between baseline measures (first visit to paediatric rheumatologist) were analysed using multiple linear regression. Linear mixed-effect models for change in the clinical measures of disease over 48 months were estimated including MFQ as an explanatory variable. Results Data from 102 patients were analysed. At baseline, median (IQR) age was 13.2 years (11.9–14.2 years) and 14.7% scored over the MFQ cut-off for major depressive disorder. At baseline, depressive symptoms significantly associated with all clinical measures of disease (P ⩽ 0.01). High baseline depressive symptoms scores predicted worse pain (P ⩽ 0.005) and disability (P ⩽ 0.001) 12 months later but not active and limited joint counts. Conclusions Adolescent patients with JIA and depressive symptoms had more active joints, pain and disability at the time of their first specialist appointment. The associations between baseline depression and both pain and disability continued for at least one year, however, this was not the case for active joint count.

BackgroundPatients with rheumatoid arthritis (RA) have an increased risk of certain solid cancers, in particular lung cancer, compared to the general population. Treatment with tumour necrosis factor (TNF) inhibitors (TNFi) may further enhance this risk.ObjectivesTo compare the risk of solid cancer in patients with RA treated with TNFi to that in patients treated with non-biologic (synthetic) disease modifying antirheumatic drugs (sDMARDs).MethodsPatients with a physician diagnosis of RA enrolled in the British Society for Rheumatology Biologics Register, a national prospective cohort study established in 2001 to monitor the long-term safety of TNFi, were followed via record linkage with the national cancer registries until first solid cancer, death, for 5 years, or until 2011. Rates of solid cancers in 11 767 patients without prior cancer who received TNFi were compared to those in 3249 patients without prior cancer treated with sDMARDs.Results427 solid cancers were reported in 52 549 patient-years follow-up for the TNFi group (81 (95% CI 74 to 89) per 10 000 patient-years) and 136 cancers were reported in 11 672 patient-years in the sDMARD cohort (117 (95% CI 98 to 138) per 10 000 patient-years). After adjusting for differences in baseline characteristics there was no difference in risk of solid cancer for TNFi compared to sDMARD treated patients: HR 0.83 (95% CI 0.64 to 1.07). There was no difference in the relative risk of cancer for any of the individual TNFi drugs.ConclusionsThe addition of TNFi to sDMARD does not alter the risk of cancer in RA patients selected for TNFi in the UK.

Objectives To investigate the suitability of the revised Illness Perception Questionnaire (IPQ‐R) for use with adolescents with a long‐term pain condition and to validate a new questionnaire for use with this age group. Design A three‐phase mixed‐methods study. Methods Phase 1 comprised in‐depth qualitative analyses of audio‐recorded cognitive interviews with 20 adolescents with juvenile idiopathic arthritis who were answering IPQ‐R items. Transcripts were coded using framework analysis. A content analysis of their intended responses to individual items was also conducted. In Phase 2, a new questionnaire was developed and its linguistic and face validity were assessed with 18 adolescents without long‐term conditions. In Phase 3, the construct validity of the new questionnaire was assessed with 240 adolescents with juvenile idiopathic arthritis. A subset of 43 adolescents completed the questionnaire a second time to assess test–retest reliability. All participants were aged 11–16 years. Results Participants described both conceptual and response format difficulties when answering IPQ‐R items. In response, the Pain Perception Questionnaire for Young People (PPQ‐YP) was designed which incorporated significant modifications to both wording and response formats when compared with the IPQ‐R. A principal component analysis of the PPQ‐YP identified ten constructs in the new questionnaire. Emotional representations were separated into two constructs, responsive and anticipatory emotions. The PPQ‐YP showed high test–retest reliability. Conclusions Symptom beliefs appear to be more salient to adolescents with a long‐term pain condition than beliefs about the illness as a whole. A new questionnaire to assess pain beliefs of adolescents was designed. Further validation work may be needed to assess its suitability for use with other pain conditions. Statement of contribution What is already known on this subject? Versions of the adult Revised Illness Perception Questionnaire (IPQ‐R) have been adapted for adolescents and children by changing item wording; however, research to assess the degree to which the underlying IPQ‐R constructs are relevant to adolescents with a long‐term condition had not been performed. What the present study adds? In adolescents, beliefs about symptoms of their condition are more salient than beliefs about the illness as a whole.Question response formats for children and young people need to take account of age‐specific abilities.A new questionnaire has been designed for adolescents with pain. It is theoretically congruent with the CS‐SRM.

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

Aim: A genetic variant has recently reached genome-wide significance for association with TNF-inhibitor response in rheumatoid arthritis patients. Here we undertake a replication study in a UK Caucasian population to test for association with TNF-inhibitor response. Materials & methods: The genetic variant, rs3794271, located within the PDE3A–SLCO1C1 locus was analyzed for correlation with treatment response using both the EULAR classification criteria and absolute change in (Δ)DAS28 scores as outcome measures. Results: Genotype data were available from 1750 TNF-inhibitor treated individuals. However, no evidence for association was observed (EULAR: p = 0.91 and ΔDAS28: p = 0.93). Furthermore, no significant associations were observed upon stratification by the anti-TNF received (p > 0.05). Conclusion: In the largest replication cohort conducted to date, no evidence for association was observed.

Anti-tumor necrosis factor (anti-TNF) antibody has revolutionized 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 therapy.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 3 studies.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 sex were associated with reduced likelihood of achieving sustained remission.Factors predicting sustained remission are seldom reported. Evidence identified in this review supports current recommendations for methotrexate coprescription 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 optimization.

Objectives To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. Methods Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. Results SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). Conclusions Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer.

The CC chemokine receptor 5 (CCR5) has been shown to be important in the recruitment of T-helper cells to the synovium, where they accumulate, drive the inflammatory process and the consequent synovitis and joint destruction. A 32 base-pair insertion/deletion variant (CCR5Δ32) within the gene leads to a frame shift and a nonfunctional receptor. CCR5Δ32 has been investigated for its association with juvenile idiopathic arthritis (JIA), with conflicting results. The aim of this study was to investigate whether CCR5Δ32 is associated with JIA in an UK population. CCR5Δ32 was genotyped in JIA cases (n=1054) and healthy controls (n=3129) and genotype and allele frequencies were compared. A meta-analysis of our study combined with previously published studies was performed. CCR5Δ32 was significantly associated with protection from developing JIA, in this UK data set (P(trend)=0.006, odds ratio (OR) 0.79 95% confidence interval (95% CI): 0.66-0.94). The meta-analysis of all published case-control association studies confirmed the protective association with JIA (P=0.001 OR 0.82 95% CI: 0.73-0.93). CCR5Δ32 is a functional variant determining the number of receptors on the surface of T cells, and it is hypothesized that the level of CCR5 expression could influence the migration of proinflammatory T cells into the synovium and thus susceptibility to JIA.

Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed.

Objectives. Anti-TNF therapy has improved outcomes for patients with highly active RA. Less is known about its effectiveness in patients with lower disease activity. The aim of this analysis is to compare the response to anti-TNF therapy between RA patients with high (DAS28 > 5.1) and moderate (DAS28 > 3.2–5.1) disease activity. Methods. A total of 4687 anti-TNF and 344 DMARD patients with high disease activity despite treatment with two standard DMARDs (including MTX) and 224 anti-TNF- and 300 DMARD-treated patients with moderate disease activity were selected from the British Society For Rheumatology Biologics Register. Mean change in HAQ over the first 12 months of enrolment was compared first between anti-TNF-treated and untreated patients in each DAS28 group, and then between anti-TNF-treated patients in the moderate and high DAS28 groups, using doubly robust estimates, adjusting for age, gender, disease duration, baseline HAQ and DAS28 score, number of previous DMARDs and steroid use. Results. Compared with anti-TNF-untreated patients within each DAS group, treated patients were younger, had higher DAS28 and HAQ and had failed a higher number of previous DMARDs. The mean adjusted change in HAQ over 12 months was similar in anti-TNF-treated patients with moderate and high disease activity at baseline: moderate −0.26 (95% CI −0.35, −0.16), high −0.28 (95% CI −0.34, −0.23) and mean difference −0.03 (95% CI −0.14, 0.08). Conclusions. Improvement in HAQ score 12 months after start of anti-TNF therapy was not dependent on baseline DAS28 scores, suggesting that substantial benefits may also be gained by treating those with moderately active disease despite standard DMARD therapy.

The WTCCC study identified 49 SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-4) - 1 x 10(-5) (tier 3). Here we show that three of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend P = 4 x 10(-5), P = 4 x 10(-4) and P = 4 x 10(-4), respectively) in a validation study of 4,106 individuals with rheumatoid arthritis and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in individuals of European ancestry.

There are currently 3 anti–tumor necrosis factor α (anti-TNFα) drugs licensed for use in rheumatoid arthritis (RA) in the UK: infliximab and adalimumab, both monoclonal antibodies, and etanercept, a TNFα receptor fusion protein. Since TNFα is involved in host defense and tumor surveillance, there have been concerns that anti-TNFα therapy might lead to adverse events, particularly infection and malignancy. These are complex issues, since RA itself increases the risk of serious infection and certain malignancies, acting either via the disease process or secondary to traditional disease-modifying antirheumatic drugs (DMARDs). The question that needs to be addressed is whether anti-TNFα therapy further increases that risk. The long-term safety of treatment with biologic response modifiers cannot, however, be addressed in short-term randomized clinical trials, not only because such trials have a limited duration, but also because they recruit insufficient numbers of patients to detect rare events. Large population-based registers are thus increasingly being used to study drug safety (1–4). A number of methodologic aspects of register study design are now well-established. There must be a comparison cohort of patients who are as similar as possible to patients in the treatment cohort, aside from taking the drug in question. Adverse events must be reported in a robust manner with avoidance of reporting bias. Information on potential confounders should be collected and adjusted for in the analysis. There are, however, obvious selection factors in determining which patients start, and indeed stop, a particular therapy, which are not necessarily captured even in intensive data sets. Residual confounding is a major concern. In 2 recently published studies from Germany and the UK (2,5), the infection rates observed in the anti-TNFα cohorts were very similar, but the 2 groups of investigators drew very different conclusions, the former estimating a doubling of risk and the latter no increased risk. These conclusions highlight important differences between the 2 countries in their methods of selecting comparison cohorts. There are also a number of issues relating to the method of analysis that are often ignored, but which need to be considered when interpreting the data from individual registers. This study examined the influence of different approaches on the analysis of serious infection rates following anti-TNFα therapy in patients with RA. The first key question is whether any increase in risk of infection is constant over time, or whether there are specific times when the risk is higher or lower. Plausible models of risk over time include increased risk of an adverse event on initial exposure, constant risk with ongoing drug exposure, or increasing risk with cumulative exposure to the drug (Figures 1a–d). The pattern of risk is likely to differ according to the adverse event considered. An infusion reaction may be more likely to occur early in the course of therapy, whereas a malignancy may be related to cumulative drug exposure. For any given adverse event, the overall risk pattern may be a composite of these patterns. Figure 1 Patterns of constancy of risk of infection while receiving treatment (on drug) and after discontinuation of treatment (off drug). a, Increased risk at start of therapy. b, Constant risk with ongoing drug exposure. c, Increasing risk with cumulative drug ... It is also necessary to define an at-risk window, that is, the period when adverse events should be attributed to a drug. The minimum plausible at-risk window would extend from the beginning of therapy to the therapy discontinuation date (Figure 2a). Defining this, however, is complex in the context of anti-TNFα therapy, given the administration schedule (with, in the case of infliximab, for example, infusions several weeks apart). In addition, depending on the pharmacokinetics and pharmacodynamics of the drug, should the at-risk window extend beyond the drug discontinuation date (Figure 2b)? The third concern is whether a drug confers a long-term risk beyond its period of pharmacologic activity. In this case, an “ever taken drug” model would be applicable (Figure 2c). In combination, these factors can have substantial influences on the measured risk. Figure 2 Influence of the definition of the at-risk period on an infection being attributed to therapy. a, Duration of treatment as the at-risk period. The at-risk window during which events can be attributed to the drug runs from 0 to 15 months. Serious infection ... Further, the risk once the patient has stopped taking the drug may take one of many patterns (Figures 1e–h). It may remain constant, may decrease back to baseline linearly or, more likely, decrease in a nonlinear manner. It is possible that risk may never return to the pretreatment baseline level. Finally, the statistical approach to analysis of changing risk pattern over time also needs to be considered. In the analysis of rare events, data may need to be aggregated, or “smoothed,” to obtain a meaningful estimate of risk over time. Interpretation of risk over time may be affected by this smoothing process. Without carefully considering these sources of variability, the simple description of infection risk as x cases per 1,000 person-years of therapy is impossible to interpret. We used a large national observational study to assess the impact of the various issues addressed above on the estimated risk of infection following anti-TNFα therapy in patients with RA.

Objective. The aim was to correlate protein concentrations of S100A9 in pretreatment serum samples with response to the tumour-necrosis factor (TNF) inhibitor drugs etanercept in a large UK replication cohort. Methods. Pretreatment serum samples from patients with RA (n = 236) about to commence treatment with etanercept had S100A9 serum concentration measured using an ELISA. Following the experimental procedure, S100A9 concentrations were analysed with respect to EULAR response. Results. No evidence of association between S100A9 concentration and EULAR response to the TNF-inhibitor biologic drug etanercept was observed following multinomial logistic regression analysis (non-responder vs moderate responder, P = 0.957; and non-responder vs good responder, P = 0.316). Furthermore, no significant associations were observed when correlating pretreatment S100A9 concentrations with clinical parameters of disease activity (P > 0.05). Conclusion. In the largest replication cohort conducted to date, no evidence for association was observed to support the use of S100A9 as a clinical biomarker predictive of response to the TNF-inhibitor biologic drug etanercept.

Approximately 30% of rheumatoid arthritis (RA) patients fail to respond to anti-tumour necrosis factor (anti-TNF) treatment;1 hence, the ability to predict which patients will respond to treatment would represent a major clinical advance. Vitamin D has been implicated in many autoimmune diseases including RA; in addition, vitamin D has been shown to induce TNFα production by some immune cells leading to the hypothesis that vitamin D levels may influence anti-TNF treatment response.2 ,3 Several studies have now confirmed the association of genetic variants within four vitamin D metabolism genes ( GC, DHCR7/NADSYN1, CYP2R1, CYP24A1 ) with circulating vitamin D levels in healthy controls.4 ,5 In addition, single nucleotide polymorphisms (SNPs) in these genes have also been associated with autoimmune diseases.6 The association of the same variants in the same genes that control circulating levels of vitamin D with response to anti-TNF treatment provides an unbiased test of the hypothesis that vitamin D levels are important in response to these therapies (Mendelian randomisation).7 We, therefore, investigated the effect of vitamin D on response to anti-TNF therapy, testing six SNPs previously associated with circulating levels of vitamin D4 ,5 for association with response to anti-TNF therapy in RA patients from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort (table 1), which includes patients recruited across the UK.8 SNPs were selected to capture by linkage disequilibrium (LD) (r2>0.8) 94.26% of SNPs previously associated with vitamin D levels in two previous studies.4 ,5 Multivariate linear and logistic regression was used to assess the effects of each SNP on treatment response measured by absolute change in Disease Activity Score in 28 joints (DAS28) over 6 months9 (n=1396) or in poor (n=237) versus good (n=322) responders according to European League …

Objective.To examine fine specificity of anticitrullinated peptide antibodies (ACPA) in relation to responsiveness to anti-tumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA).Methods.Samples from 450 patients with RA treated with anti-TNF agents were analyzed for antibodies to citrullinated α-enolase, vimentin, and fibrinogen peptides. The Disease Activity Score-28 was measured at baseline and 6 months.Results.Both anti-cFib antibodies and the number of citrullinated peptides recognized were associated with a poorer response. These findings were not significant following stratification for anti-cyclic citrullinated peptide 2 antibodies.Conclusion.The presence of any ACPA rather than individual ACPA specificities was associated with a poorer response to anti-TNF agents. We suggest that this reflects distinctive differences in the pathogenesis of ACPA-positive and negative RA.

Objective To explore the influence of anti-tumor necrosis factor (anti-TNF) therapy upon the incidence of cancer in patients with rheumatoid arthritis (RA) and prior malignancy. Methods Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study established in 2001, we identified 293 patients with a prior malignancy from over 14,000 patients with RA. We compared rates of incident malignancy in 177 anti-TNF-treated patients and 117 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs), all with prior malignancy. One patient switched therapy and contributed to both cohorts. Results The rates of incident malignancy were 25.3 events/1,000 person-years in the anti-TNF cohort and 38.3/1,000 person-years in the DMARD cohort, generating an age- and sex-adjusted incidence rate ratio of 0.58 (95% confidence interval 0.23-1.43) for the anti-TNF-treated cohort compared with the DMARD cohort. Of the patients with prior melanomas, 3 (18%) of 17 in the anti-TNF cohort developed an incident malignancy, compared with 0 of 10 in the DMARD cohort. Conclusion The way in which UK rheumatologists are selecting patients with RA and prior malignancy to receive anti-TNF therapy is not leading to an increased risk of incident malignancy. Although reassuring, these results should not be interpreted as indicating that it is safe to treat all RA patients with prior malignancy with anti-TNF therapy.

OBJECTIVE: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS: A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. RESULTS: Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). CONCLUSION: Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections

The introduction of anti-tumour necrosis factor (TNF) agents has greatly improved the treatment of rheumatoid arthritis; however, a significant proportion of patients fail to respond to therapy. We hypothesized that genes within the TNF receptor superfamily member 1B signalling pathway contribute towards the observed variation in patient response. This was tested by genotyping 73 single-nucleotide polymorphisms (SNPs) from six candidate genes (DUSP1, HRB, IKBKAP, MAP3K1, MAP3K14 and TANK) in a large UK cohort of rheumatoid arthritis patients (n=642). Two SNPs [rs96844 (MAP3K1) and rs4792847 (MAP3K14)] showed evidence of association (P