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Background/Aims Psychological distress is prevalent in people with inflammatory arthritis. In populations with axial spondyloarthritis (SpA), the risk of developing mental ill-health is high - for depression more than twice that of control populations. Positive emotions are protective against psychological distress and emotional wellbeing is favourably associated with physical illness prognosis. However, the emotional experiences of people who live with axial SpA are not well understood. This study aimed to explore and synthesise qualitative data about the emotional experience of living with axial SpA and identify barriers and facilitators to emotional wellbeing. Methods First, a systematic review and thematic synthesis was conducted. Nine databases were searched from inception to December 2019. Qualitative and mixed methods studies were included if they reported qualitative participant level data about the lived emotional experiences of people with axial SpA and were published in English or German. The search was updated in March 2021. Study quality was assessed using a modified version of the CASP (Critical Appraisal Skills Programme) qualitative tool. Grey literature was appraised using the Authority, Accuracy, Coverage, Objectivity, Date, Significance (AACODS) checklist. Data were extracted, coded and categorised. Synthesis involved translation of concepts from one study into another and development of descriptive themes. Second, four axial SpA online forums were searched from inception to June 2020 for posts from UK-based individuals with axial SpA containing data about their emotional experiences of axial SpA. Thematic analysis was undertaken. Results Of 10,824 database records screened, 27 studies, published between 1995 and 2020, went forward for synthesis. Study populations included people diagnosed with Ankylosing Spondylitis (n = 1143), axial SpA (n = 53) and non-radiographic axial SpA (n = 18). Two studies with mixed populations (n = 37) did not specify numbers diagnosed with axial SpA. Most participants were male and had established disease. No studies specifically focused on the psychological experiences of living with axial SpA. 537 posts were identified from online fora, 278 (52%) of which were from men. Seven descriptive themes were generated from the qualitative synthesis: delayed diagnosis: a barrier to emotional wellbeing; disruptive symptoms: a source of mood swings; work disability: a loss of self-esteem; obstacles in interpersonal relationships: a trigger of distress; taking up exercise: ‘personal pride’ or ‘unwelcomed reminders’; anti-TNF therapy: hope reignited despite concerns; journey of acceptance: worry mixed with hope. The findings from our review of online fora supported and validated these themes. One additional theme - COVID-19: uncertainty and anxiety during the pandemic - was developed from constructs identified from online posts. Conclusion Our findings highlight substantial negative and mixed emotions experienced by people with axial SpA. However, data about the emotional experiences of women, people diagnosed with non-radiographic axial SpA, and those in the early stages of diagnosis, are limited. Disclosure N. Wilson: None. J. Liu: None. Q. Adamjee: None. S. Di Giorgio: None. S. Steer: None. H. Lempp: None.

Background Rising healthcare demand for people with rheumatic and musculoskeletal diseases in the UK is set to continue. Delivering sustainable outpatient rheumatology services, with a shift towards remote patient monitoring, virtual consultations, shared decision-making and supported self-management, is now a key NHS priority. Involving patients in outpatient rheumatology services transformation is considered a core prerequisite for success; a first step being to understand the perspectives of and preferences for care of patients with rheumatic and musculoskeletal diseases. Current evidence of perceived health service needs in people with inflammatory arthritis centres on rheumatoid arthritis; understanding about perceptions of people with axial spondyloarthritis (axSpA), in particular younger adults, is limited. The aim of this qualitative study was to explore in depth the experiences of, and preferences for, the delivery of NHS outpatient rheumatology services in adults diagnosed with AxSpA. Methods Five semi-structured focus groups were conducted between 2018 and 2019 with younger (age Results Thirty-three adults with AxSpA (18 men and 15 women) from diverse ethnic backgrounds and with a range of disease-related characteristics participated in the study. Thirteen participants were aged Conclusion Focus group members described a picture of inconsistent delivery of NHS rheumatology outpatient services in the UK. Preferences for care in adults with AxSpA largely align with proposals to transform NHS outpatient services and revolve around flexible delivery of patient-centred consultations, underpinned by shared decision-making and supported self-management. However, integrating these preferences into new models of care delivery to ensure optimal patient outcomes will require transformative action. These data can inform local and national developments to reconfigure outpatient services for people with AxSpA. Disclosures N. Wilson None. N. Kaiser None. J. Roose None. R. Martinez None. S. Steer None. H. Lempp None.

Background We live in an age where digital interactions are the norm. These may take the form of communication with friends and family, social media, contacting your bank or reading the daily news. Most of our rheumatology patients have smartphones or other digital platforms to access these. Healthcare, however, lags in adopting technology. Digital health solutions such as 'GP at hand' (Babylon) are still seen as disruptive market innovations. NHS improvement would like to reduce face-to-face activity by 10% through forms of digital enablement. We set out to develop our own platform, using a smartphone-enabled app. The aim is to remotely support a patient’s self-management, collect patient reported outcomes (PROMs) and facilitate patient-department communication. We describe the development of the app and early experience of use. Methods We conducted stakeholder meetings with expert patients, clinicians and app developers. In 2015 we launched a pilot app. Following user feedback, a full version of the app was launched in September 2018. In compliance with EU General Data Protection Regulation (GDPR) laws, it currently works as a standalone tool separate to hospital Electronic Health Record (EHR) systems at King's College Hospital. App awareness took place through clinic appointments and a patient educational event. Patients download and register through Android or iOS operated devices. Basic information and explicit consent for data use are gathered. Data are stored on a cloud-based platform accessible to the clinical team and extracts anonymised for analysis. Results 301 patients registered with the app in the first year since launch. Mean age was 44 years (Median 42.5 (IQR 35-53), Range 16-76) slightly younger than that of our local cohort. Clinical enquiries recorded via email have steadily increased since the app’s inception, rising from 2 throughout September 2018 to 209 in September 2019. Almost 25% of patients entered PROMs. These were performed on 115 occasions by 70 different patients (Median 1, Range 1-12). 52 (17.3%) patients used the app to store medication reminders. User feedback has identified positive aspects: links to patient education resources, medication reminders and rapid direct clinical communication. Negative aspects include: no link to the EHR system, inability to change or view appointments, inability to request blood tests. Conclusion We have demonstrated in this project that an app is feasible to use in a rheumatology clinical practice setting, providing a mechanism for collecting patient information and enabling self-management. Use of healthcare apps is clearly not for everyone, with only a minority of our patients using our platform. For apps to be sustainable they need to be of targeted benefit with proportionate investment. A key future strategy is to strengthen our self-management interface and integrate with our EHR systems. Disclosures B.D. Clarke None. L. James None. H. Lapham None. C. Congreve None. S. Steer None. N. Alaghband None. J.B. Galloway Grants/research support; J.G. receives a grant from Pfizer to support the development of this app.

Background The National Health Service caters to a variety of rheumatology patients from increasingly diverse multi-ethnic backgrounds. Despite this, societal, organisational and personal barriers remain across the UK. These are known to directly and indirectly influence access to care although no inference can be generalised at a local level. Our south London trust has one of the highest non-white patient bases in the UK, hence our interest in wanting to explore the cultural differences around delivery of care. We set out to use the national inflammatory arthritis audit (NEIAA) data from our department to ensure equitable service provision and delivery using quality improvement methodology. Methods The NEIAA data for our trust observes performance across the seven NICE quality indicators for rheumatoid arthritis. Of interest was evaluation of standards 1 to 6, as too few data existed for standard 7. Ethnicity was coded according to the NEIAA categories as white or non-white. Differences by disease severity indicators were analysed. A descriptive analysis was performed with an understanding that no assumptions or statistical interpretations could be made to these observed differences. Results A total of 471 patients had data available. Of these, 124 (26%) had a diagnosis of early inflammatory arthritis, of whom 34 (27%) were non-white and 80 (73%) were white. Non-white patients were younger, more were seropositive, had a higher baseline DAS28, worse MSK-HQ scores, worse mental health scores and worse HAQ scores. Non-white patients were less likely to have a patient reported outcome recorded. Attainment of quality standards 1, 2, 3 and 6 had equiproportionate representation of non-white and white patients. Standards 4 (provision of education) and 5 (agreement of treatment target) demonstrated fewer non-white patients meeting the target. Standard 5 demonstrated the most disparity. 83% of white patients had an agreed target compared to 47% of non-white (Odds ratio 5.6 (CI 2.2-14.1)). To describe this, our non-white patients were more than 5 times less likely to have an agreed treatment target. Conclusion Cultural differences exist in health-seeking behaviour, verbal language, written comprehension and in unconscious bias. The NEIAA results within our trust suggest differences exist by ethnic groupings in early arthritis care. Although challenges and taboos remain in discussing these variations, more work needs to be undertaken to explore healthcare disparities and why these occur. Research within this field is limited to date. We plan to adopt a quality improvement approach using stakeholder engagement meetings, process-mapping and driver diagrams to evaluate how best to achieve change. Disclosures L. James None. B.D. Clarke None. R. Salerno None. A. Audu None. S. Steer None. J.B. Galloway None.

Background\ud Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants.\ud \ud Methods\ud Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases.\ud \ud Results\ud In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P

Rheumatoid Arthritis (RA) pharmacotherapy may impact mental health (MH) outcomes by improving pain and stiffness; and potentially via targeting inflammatory processes common to RA and depression. The objectives of this review were to i) ascertain the frequency of MH assessment in RA pharmacotherapy trials; ii) quantify the efficacy of RA pharmacotherapy efficacy on MH outcomes; iii) explore the clinical and demographic factors related to MH outcomes.\ud \ud CENTRAL, PsychINFO, Web of Science, Medline, Embase and CINAHL were systematically searched from inception to March 2017 for randomised trials of disease‐modifying anti‐rheumatic drugs (DMARDs) in adult RA patients. The primary outcome was MH; self‐reported physical health was extracted as a secondary outcome. Pairwise meta‐analysis (PMA) created pooled effect sizes and 95%CIs for comparisons of all treatments versus comparators (active or placebo). Network meta‐analysis (NMA) provided effect size estimates of targeted biologic DMARDs (bDMARDs) versus conventional synthetic DMARDs (csDMARDs) using indirect comparisons of different treatment modalities.\ud \ud 71 eligible studies were identified. 57 studies were included in the PMA, representing 23,535 patients. bDMARDs showed small effects on MH (standardised mean difference (SMD) versus csDMARDs = 0.19 to 0.30), and moderate effects on self‐reported physical health (SMD versus csDMARDs = 0.46 to 0.50), with NMA determining no significant differences in effectiveness between bDMARD mode of action on either outcome.\ud \ud Effective pharmacotherapy alone is unlikely to substantially improve MH outcomes for most RA patients. Integrated MH care provided within routine clinical practice is essential to optimise mental and physical health outcomes.

Objective. The aim of this analysis is to examine the longitudinal impact of symptoms of depression/anxiety on treatment response, long-term disease activity and physical disability in RA.Methods. Secondary analysis of clinical trial data was performed. Data were collected at baseline and at 6-monthly intervals for 2 years. The EuroQoL (EQ-5DTM) indicated depression/anxiety symptom severity. Our primary outcomes of interest were (i) DAS-28 and (ii) physical disability measured via the HAQ. Secondary outcomes were: tender and swollen joint counts, patient global assessment, ESR and odds of reaching clinical remission. Multilevel models were used to assess the impact of baseline and persistent depression/anxiety on outcomes over 2 years.Results. Data from 379 patients were included. After adjusting for covariates, baseline depression/anxiety symptoms were associated with increased DAS-28 outcomes and increased tender joint counts. Persistent depression/anxiety symptoms were associated with increased DAS-28 scores, HAQ scores, tender joint counts and patient global assessment of disease activity, and reduced odds of reaching clinical remission. Patients with symptoms of depression/anxiety at baseline also showed a 50% reduction in prednisolone treatment effect, in comparison with patients with no symptoms of depression/anxiety at baseline.Conclusion. Baseline and persistent symptoms of depression/anxiety are associated with poorer health outcomes over time, as well as reduced treatment response. Mental health should be routinely measured both in clinical practice and in research, and managed alongside rheumatological disease to optimize health outcomes. Further research is required to examine whether treatment of mental disorders can improve rheumatological outcomes.

Objective.Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA.Methods.We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants — 69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions — for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models.Results.HLA variants were associated with joint destruction. The *04:01 SNP (rs660895, p = 0.0003), *04:01 allele (p = 0.0002), and HLA-DRβ1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP — rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004) — associated with HAQ scores over 6–24 months.Conclusion.HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.

ObjectiveThe assessment of health-related quality-of-life (HRQoL) in rheumatoid arthritis (RA) is becoming increasingly common in both research and clinical practice. One of the most widely used tools for measuring HRQoL is the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). We conducted a systematic review examining the impact of RA on HRQoL, measured through the SF-36.MethodsMEDLINE and Embase were searched for observational studies reporting mean and standard deviation scores for each domain of the SF-36 in adult RA patients. Studies were reviewed in accordance with PRISMA guidelines, and a random-effects meta-analysis was performed.ResultsIn total, 31 studies were eligible for inclusion in the meta-analysis, including 22,335 patients. Meta-analyses found that pooled mean HRQoL score for the SF-36 physical component summary was 34.1 (95% CI: 22.0–46.1) and mental component summary was 45.6 (95% CI: 30.3–60.8). Increased age was associated with reduced physical function and physical component summary (PCS) scores but improved mental health and mental component summary (MCS) scores. Female gender was associated with improved scores on role physical, bodily pain and PCS but reduced mental health and MCS scores. Longer disease duration was associated with improved MCS. Patients with RA have a substantially reduced HRQoL in comparison to both other physical illnesses and in comparison to normative datasets from UK and USA populations.ConclusionsRA has a substantial impact on HRQoL. This supports recent NICE guidelines stipulating that RA patients should be regularly assessed for the impact their disease has on HRQoL and appropriate management provided.

Objective The number of confirmed rheumatoid arthritis (RA) loci currently stands at 32, but many lines of evidence indicate that expansion of existing genome-wide association studies (GWAS) enhances the power to detect additional loci. This study was undertaken to extend our previous RA GWAS in a UK cohort, adding more independent RA cases and healthy controls, with the aim of detecting novel association signals for susceptibility to RA in a homogeneous UK cohort. Methods A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, with the extension adding 1,361 cases and 2,334 controls to the original GWAS data set. The genotype data for all RA cases were imputed using the Impute program version 2. After stringent quality control thresholds were applied, 3,034 cases and 5,271 controls (1,831,729 single-nucleotide polymorphisms [SNPs]) were available for analysis. Association testing was performed using Plink software. Results The analyses indicated a suggestive association with susceptibility to RA (P < 0.0001) for 6 novel RA loci that have been previously found to be associated with other autoimmune diseases; these 6 SNPs were genotyped in independent samples. Two of the associated loci were validated, one of which was associated with RA at genome-wide levels of significance in the combined analysis, identifying a novel RA locus at 22q12 (P = 6.9 × 10−9). In addition, most of the previously known RA susceptibility loci were confirmed to be associated with RA, and for 16 of the loci, the strength of the association was increased. Conclusion This study identified a new RA locus mapping to 22q12. These results support the notion that increasing the power of GWAS enhances novel gene discovery.

Objective A recent high-density fine-mapping (ImmunoChip) study of genetic associations in rheumatoid arthritis (RA) identified 14 risk loci with validated genome-wide significance, as well as a number of loci showing associations suggestive of significance (P = 5 × 10−5 < 5 × 10−8), but these have yet to be replicated. The aim of this study was to determine whether these potentially significant loci are involved in the pathogenesis of RA, and to explore whether any of the loci are associated with a specific RA serotype. Methods A total of 16 single-nucleotide polymorphisms (SNPs) were selected for genotyping and association analyses in 2 independent validation cohorts, comprising 6,106 RA cases and 4,290 controls. A meta-analysis of the data from the original ImmunoChip discovery cohort and from both validation cohorts was carried out, for a combined total of 17,581 RA cases and 20,160 controls. In addition, stratified analysis of patient subsets, defined according to their anti–cyclic citrullinated peptide (anti-CCP) antibody status, was performed. Results A significant association with RA risk (P < 0.05) was replicated for 6 of the SNPs assessed in the validation cohorts. All SNPs in the validation study had odds ratios (ORs) for RA susceptibility in the same direction as those in the ImmunoChip discovery study. One SNP, rs72928038, mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (P = 1.2 × 10−8, OR 1.12), and a second SNP, rs911263, mapping to an intron of RAD51B, was significantly associated in the anti-CCP–positive RA subgroup (P = 4 × 10−8, OR 0.89), confirming that both are RA susceptibility loci. Conclusion This study provides robust evidence for an association of RA susceptibility with genes involved in B cell differentiation (BACH2) and DNA repair (RAD51B). The finding that the RAD51B gene exhibited different associations based on serologic subtype adds to the expanding knowledge base in defining subgroups of RA.

Objective. There is substantial uncertainty regarding the prevalence of depression in RA. We conducted a systematic review aiming to describe the prevalence of depression in RA.Methods. Web of Science, PsycINFO, CINAHL, Embase, Medline and PubMed were searched for cross-sectional studies reporting a prevalence estimate for depression in adult RA patients. Studies were reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and a meta-analysis was performed.Results. A total of 72 studies, including 13 189 patients, were eligible for inclusion in the review. Forty-three methods of defining depression were reported. Meta-analyses revealed the prevalence of major depressive disorder to be 16.8% (95% CI 10%, 24%). According to the PHQ-9, the prevalence of depression was 38.8% (95% CI 34%, 43%), and prevalence levels according to the HADS with thresholds of 8 and 11 were 34.2% (95% CI 25%, 44%) and 14.8% (95% CI 12%, 18%), respectively. The main influence on depression prevalence was the mean age of the sample.Conclusion. Depression is highly prevalent in RA and associated with poorer RA outcomes. This suggests that optimal care of RA patients may include the detection and management of depression.

Rheumatoid arthritis (RA) is a heterogeneous disease that varies markedly in its severity. There is, therefore, a key research need to develop methods that can predict an individual’s likely RA severity at disease onset, which would enable treatment to be tailored accordingly. A number of different prognostic factors for RA severity have been identified. These include environmental (such as smoking and alcohol consumption), genetic (such as the HLA-DRB1 alleles and polymorphisms in the IL1 locus), serological (rheumatoid factor and antibodies to citrullinated protein antigens) and biochemical (such as matrix metalloproteinases) factors. In this review, the authors discuss these prognostic factors in detail, outlining the evidence supporting them and focusing on how they have been combined in prognostic modeling to predict the likely severity of an individual’s RA phenotype.

Background Polymorphisms of the peptidylarginine deiminase type 4 ( PADI4 ) gene confer susceptibility to rheumatoid arthritis (RA) in East Asian people. However, studies in European populations have produced conflicting results. This study explored the association of the PADI4 genotype with RA in a large UK Caucasian population. Methods The PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian patients with RA (n=3732) and population controls (n=3039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was used to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1859) and controls (n=10 599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study. Results The PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all the cases of RA (n=5591) and controls (n=13 638) gave an overall OR of 1.01 (95% CI 0.96 to 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between the PADI4_94 genotype and RA in people of European descent (OR 1.06, 95% CI 0.99 to 1.13, p=0.12). Conclusion In the largest study performed to date, the PADI4 genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations.

OBJECTIVE: To define interactions between the HLA-DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody- and rheumatoid factor (RF)-positive and -negative rheumatoid arthritis (RA). METHODS: Data on approximately 5,000 RA patients and approximately 3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody-positive and -negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel-Haenszel analysis. Analyses of the combined effects of PTPN22, HLA-DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework. RESULTS: The combined effects of PTPN22, HLA-DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio [OR] 11.1, P < 0.0001), whereas only HLA-DRB1 SE and smoking were independently associated with RF production (OR 4.4, P < 0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001). CONCLUSION: PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA-DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene-environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.

Objective Rheumatoid arthritis (RA) is a common disabling autoimmune disease with a complex genetic component. We have previously described linkage of a region of chromosome 8q12.3 with RA and association of the microsatellite marker CRHRA1 with RA in 295 affected sibling-pair families. In the current study we aimed to physically link the RA-associated marker with the corticotropin-releasing hormone (CRH) candidate gene, and to examine the genomic region for additional short tandem repeat (STR) genetic markers in order to clarify the association with RA. Methods We examined the association of 2 STR markers with disease in the original 295 multicase families and in a cohort of 131 simplex families to refine our understanding of this genetic region in disease susceptibility in sporadic and familial RA. Genomic library screening and sequencing were used to generate physical sequences in the CRH genomic region. Bioinformatic analysis of the sequence flanking the CRH structural gene was used to screen for additional STRs and other genetic features. Genotyping was carried out using a standard fluorescence approach. Estimations of haplotype frequencies were performed to assess linkage disequilibrium. The transmission disequilibrium test was performed using TRANSMIT. Results Physical cloning and sequencing analyses identified the genomic region linking the CRHRA1 marker and the CRH structural locus. Moreover, we identified a further STR, CRHRA2, which was in strong linkage disequilibrium with CRHRA1 (P = 4.0 × 10−14). A haplotype, CRHRA1*10;CRHRA2*14, was preferentially carried by unaffected parents at a frequency of 8.6% compared with the expected frequency of 3.1%. This haplotype was overtransmitted in the multiply affected families (P = 0.0077) and, similarly, in the simplex families (P = 0.024). Combined analysis of both family cohorts confirmed significant evidence for linkage (P = 4.9 × 10−4) and association (P = 5.5 × 10−3) for this haplotype with RA. Conclusion In demonstrating significant linkage disequilibrium between these 2 markers, we have refined the disease-associated region to a single haplotype and confirmed the significance of this region in our understanding of the genetics of RA.

Background This study aimed to assess the accuracy of the Short-Form Health Survey (SF-36) mental health subscale (MH) and mental component summary (MCS) scores in identifying the presence of probable major depressive or anxiety disorder in patients with rheumatoid arthritis. Methods SF-36 data were collected in 100 hospital outpatients with rheumatoid arthritis. MH and MCS scores were compared against depression and anxiety data collected using validated measures as part of routine clinical practice. Sensitivity and specificity of the SF-36 were established using receiver operating characteristic (ROC) curve analysis, and area under the curve (AUC) compared the performance of the SF-36 components with the 9-item Patient Health Questionnaire (PHQ9) for depression and the 7-item Generalised Anxiety Disorder (GAD7) questionnaire for anxiety. Results The MH with a threshold of ≤52 had sensitivity and specificity of 81.0 and 71.4 % respectively to detect anxiety, correctly classifying 73.5 % of patients with probable anxiety disorder. A threshold of ≤56 had sensitivity and specificity of 92.6 and 73.2 % respectively to detect depression, correctly classifying 78.6 % of patients, and the same threshold could also be used to detect either depression or anxiety with a sensitivity of 87.9 %, specificity of 76.9 % and accuracy of 80.6 %. The MCS with a threshold of ≤35 had sensitivity and specificity of 85.7 and 81.9 % respectively to detect anxiety, correctly classifying 82.8 % of patients with probable anxiety disorder. A threshold of ≤40 had sensitivity and specificity of 92.3 and 70.2 % respectively to detect depression, correctly classifying 76.3 % of patients. A threshold of ≤38 could be used to detect either depression or anxiety with a sensitivity of 87.5 %, specificity of 80.3 % and accuracy of 82.8 %. Conclusion This analysis may increase the utility of a widely-used questionnaire. Overall, optimal use of the SF-36 for screening for mental disorder may be through using the MCS with a threshold of ≤38 to identify the presence of either depression or anxiety. Electronic supplementary material The online version of this article (doi:10.1186/s12891-016-1083-y) contains supplementary material, which is available to authorized users.

BACKGROUND: Rheumatoid arthritis (RA) treatment paradigms have shifted over the last two decades. There has been increasing emphasis on combination disease modifying anti-rheumatic drug (DMARD) therapy, newer biologic therapies have become available and there is a greater focus on achieving remission. We have evaluated the impact of treatment changes on disease activity scores for 28 joints (DAS28) and disability measured by the health assessment questionnaire scores (HAQ).METHODS: Four cross-sectional surveys between 1996 and 2014 in two adjacent secondary care rheumatology departments in London evaluated changes in drug therapy, DAS28 and its component parts and HAQ scores (in three surveys). Descriptive statistics used means and standard deviations (SD) or medians and interquartile ranges (IQR) to summarise changes. Spearman's correlations assessed relationships between assessments.RESULTS: 1324 patients were studied. Gender ratios, age and mean disease duration were similar across all cohorts. There were temporal increases in the use of any DMARDs (rising from 61% to 87% of patients from 1996-2014), combination DMARDs (1% to 41%) and biologic (0 to 32%). Mean DAS28 fell (5.2 to 3.7), active disease (DAS28 > 5.1) declined (50% to 18%) and DAS28 remission (DAS28 CONCLUSIONS: Treatment intensity has increased over time, disease activity has fallen and there are more remissions. However, these improvements in controlling synovitis have not resulted in comparable reductions in disability measured by HAQ. As a consequence the relationship between DAS28 and HAQ has become weaker over time. Although the reasons for this divergence between disease activity and disability are uncertain, focussing treatment entirely in suppressing synovitis may be insufficient.

Rheumatoid arthritis (RA) varies over time in individual patients and there are marked differences between patients in its impact and progression. The course of RA is therefore unique to each individual patient and is affected by the overall pattern of disease; many patients have classical polyarticular disease but there is also a range of subtypes, such as fibromyalgic and polymyalgic disease. Some patients with RA enter a period of sustained remission; this varies between 10% and 36% of cases; its frequency is mainly influenced by the different approaches to studying RA patients over time, and does not represent a true difference in disease outcome. Most patients have persisting synovial inflammation and disease activity scores average between 3 and 4; there is some evidence that inflammation is less marked in late RA. Persisting synovitis results in increasing disability - this worsens by an average of 0.6% each year - and in joint damage, which increases by an average of 2% each year. Comorbidities and extra-articular features are commonplace: about one-third of patients, respectively, have associated cardiovascular disease, lung disease or extra-articular features, although severe extra-articular problems like vasculitis affect only about 10% of patients. Some aspects of the course of RA are influenced by genetic risks; currently these are only weak predictors but it is anticipated their value will increase with time.

Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation.To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles.WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed.Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls.The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.

Our aim was to establish whether alcohol protects against RA development and to determine whether this effect is influenced by alcohol dose, duration and serological status through systematically reviewing the literature and undertaking a meta-analysis.We searched Medline/EMBASE (1946 to July 2012) using the terms rheumatoid arthritis.mp or arthritis, rheumatoid/ and alcohol.mp or ethanol/. Manuscript bibliographies were reviewed. Observational studies were included that were case-control/cohort, examined the relationship between alcohol and RA risk and reported or allowed the calculation of effect size data [odds ratios (ORs)/relative risks (RRs) with 95% CIs] in drinkers vs non-drinkers. A random-effects model was used to estimate pooled ORs/RRs. Dose-risk relationships were evaluated by trend tests. RESULTS. Nine studies (from 893 articles) met our inclusion criteria, comprising six case-control (3564 cases; 8477 controls) and three cohort studies (444 RA cases; 84 421 individuals). A significant protective effect of alcohol on RA risk was observed-summary OR for RA in drinkers vs non-drinkers 0.78 (95% CI 0.63, 0.96). This effect was confined to ACPA-positive RA-summary OR 0.52 (95% CI 0.36, 0.76), with no significant risk reduction seen for ACPA-negative RA-summary OR 0.74 (95% CI 0.53, 1.05). Subgroup analysis by study design identified a significant relationship in case-control but not cohort studies.Alcohol intake is inversely associated with ACPA-positive RA, suggesting a protective effect. As this finding is confined to case-control studies further research is required with prospective cohort studies incorporating ACPA status to confirm this relationship.

The IL-23R region is associated with a number of non-infectious inflammatory conditions including inflammatory bowel disease, ankylosing spondylitis and psoriasis,1,–,3 and albeit with less consistent evidence, rheumatoid arthritis (RA).4,–,6 Association of rs1343151 (G→A) with RA, but not rs1004819/rs10489629/rs2201841 , has been reported in European and New Zealand sample sets;5 none of rs3212227/rs6887695/rs7530511 was associated in European and North American sample sets,6 and rs7517847 was not associated in meta-analysed European and New Zealand sample sets.4 Given the immunological evidence pointing to the importance of the Th17–IL-23 axis in inflammation and autoimmunity,7 and the unresolved question of whether or not IL-23R is associated with RA, we further investigated association of IL-23R with RA in white European Caucasian case–control sample sets (cases ascertained …

Rheumatoid arthritis (RA) is considered to occur when genetic and environmental factors interact to trigger immunopathological changes and consequently an inflammatory arthritis. Over the last few decades, epidemiological and genetic studies have identified a large number of risk factors for RA development, the most prominent of which comprise cigarette smoking and the shared epitope alleles. These risks appear to differ substantially between anti-cyclic citrullinated peptide (ACPA)-positive and ACPA-negative disease. In this article, we will summarise the risk factors for RA development that have currently been identified, outlining the specific gene-environment and gene-gene interactions that may occur to precipitate and perpetuate autoimmunity and RA. We will also focus on how this knowledge of risk factors for RA may be implemented in the future to identify individuals at a high risk of disease development in whom preventative strategies may be undertaken.

Contains fulltext : 98409.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Recently, a functional PTPN22 variant (R263Q; rs33996649) was found to be associated with systemic lupus erythematosus (SLE). This study was undertaken to analyze the influence of this polymorphism on the risk of rheumatoid arthritis (RA). METHODS: RA patients (n = 5,579) were recruited from outpatient clinics from 6 different countries (Spain, New Zealand, the UK, Norway, The Netherlands, and Germany). Healthy controls (n = 5,392) were recruited from the same areas. There was 100% power to detect an effect equivalent to that observed in SLE. Samples were genotyped for the PTPN22 R263Q (rs33996649) and PTPN22 R620W (rs2476601) polymorphisms using a TaqMan 5'-allele discrimination assay. The effect of the R263Q variant was analyzed in isolation and in combination with the effect of R620W, using Unphased and Stata 10 software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. RESULTS: The minor allele A of PTPN22 R263Q was significantly associated with a lower risk of RA in the pooled analysis of the 6 populations (P = 0.016, Mantel-Haenszel pooled OR 0.80 [95% CI 0.67-0.96]), independent of the effect of the R620W polymorphism. Both polymorphisms had an additive effect. The more RA risk alleles carried (R263Q G allele, R620W T allele), the higher the RA risk (for 2 versus 1 risk allele P = 0.014, OR 1.28 [95% CI 1.05-1.55], for 3 versus 1 risk allele P = 6.67 x 10(-11) , OR 2.01 [1.63-2.48], and for 4 versus 1 risk allele P = 6.50 x 10(-11) , OR 3.55 [2.42-5.20]). CONCLUSION: Our findings indicate that the minor allele of the PTPN22 R263Q polymorphism is associated with a lower risk of RA. This association is independent of the well-established association between PTPN22 R620W and RA. Both polymorphisms have an additive effect on the risk of RA.

Genome-wide association studies (GWAS) have heralded a major breakthrough in the search for genes underlying rheumatoid arthritis (RA). Indeed, GWAS in UK, US and Swedish populations have identified a number of confirmed RA loci.1 Recently, a modestly-sized GWAS was undertaken in a Spanish population comprising 400 patients with RA and 400 controls.2 Association with the KLF12 gene was detected (p=6.5×10−6) and subsequently replicated in an independent cohort of 410 Spanish patients with RA and 394 controls (p=0.01). The most strongly associated single nucleotide polymorphism (SNP) was rs1324913 mapping to intron 1 of the KLF12 gene. The KLF12 protein is a repressor for a transcriptional regulatory factor, AP-2α, which has been implicated in the control of inflammation. Other SNPs at this locus also showed weak evidence for association with RA in UK …

Objective A recent meta-analysis of published genome-wide association studies (GWAS) in populations of European descent reported novel associations of markers mapping to the CD40, CCL21 and CDK6 genes with rheumatoid arthritis (RA) susceptibility while a large-scale, case-control association study in a Japanese population identified association with multiple single nucleotide polymorphisms (SNPs) in the CD244 gene. The aim of the current study was to validate these potential RA susceptibility markers in a UK population. Methods A total of 4 SNPs (rs4810485 in CD40, rs2812378 in CCL21, rs42041 in CDK6 and rs6682654 in CD244) were genotyped in a UK cohort comprising 3962 UK patients with RA and 3531 healthy controls using the Sequenom iPlex platform. Genotype counts in patients and controls were analysed with the chi(2) test using Stata. Results Association to the CD40 gene was robustly replicated (p=2 x 10(-4), OR 0.86, 95% CI 0.79 to 0.93) and modest evidence was found for association with the CCL21 locus (p=0.04, OR 1.08, 95% CI 1.01 to 1.16). However, there was no evidence for association of rs42041 (CDK6) and rs6682654 (CD244) with RA susceptibility in this UK population. Following a meta-analysis including the original data, association to CD40 was confirmed (p=7.8 x 10(-8), OR 0.87 (95% CI 0.83 to 0.92). Conclusion In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus.

INTRODUCTION: Genome wide association studies, replicated by numerous well powered validation studies, have revealed a large number of loci likely to play a role in susceptibility to many multifactorial diseases. It is now well established that some of these loci are shared between diseases with similar aetiology. For example, a number of autoimmune diseases have been associated with variants in the PTPN22, TNFAIP3 and CTLA4 genes. Here we have attempted to define overlapping genetic variants between rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CeD). METHODS: We selected eight SNPs previously identified as being associated with CeD and six T1D-associated SNPs for validation in a sample of 3,962 RA patients and 3,531 controls. Genotyping was performed using the Sequenom MassArray platform and comparison of genotype and allele frequencies between cases and controls was undertaken. A trend test P-value < 0.004 was regarded as significant. RESULTS: We found statistically significant evidence for association of the TAGAP locus with RA (P = 5.0 × 10-4). A marker at one other locus, C1QTNF6, previously associated with T1D, showed nominal association with RA in the current study but did not remain statistically significant at the corrected threshold. CONCLUSIONS: In exploring the overlap between T1D, CeD and RA, there is strong evidence that variation within the TAGAP gene is associated with all three autoimmune diseases. Interestingly a number of loci appear to be specific to one of the three diseases currently studied suggesting that they may play a role in determining the particular autoimmune phenotype at presentation.

Genome-wide association studies (GWAS) have contributed to the identification of at least 14 rheumatoid arthritis (RA) susceptibility loci.1 One of the first RA GWAS included 1522 cases and 1850 controls from the USA/Sweden and identified TRAF1/C5 as a novel RA locus.2 This GWAS was recently repeated after including an additional 1550 cases and 3310 controls from the USA and restricting analysis to US subjects.3 In the expanded sample, two novel single nucleotide polymorphisms (SNP) mapping to the REL locus showed association with RA. REL encodes c-Rel, a member of the nuclear factor kappa B family of transcription factors and one of the associated SNP (rs13031237) maps to an intron of this gene. The association was validated in an independent sample of 2604 RA cases and 2882 controls from the USA/Canada, with strong evidence for association in the combined samples (rs13031237, p=3.1×10−14). We aimed to test the …

Updated guidance from the UK National Institute for Health and Clinical Excellence on the use of tumor necrosis factor (TNF) antagonists for rheumatoid arthritis recommends that patients who do not respond to initial anti-TNF therapy should not switch to another TNF inhibitor. In this Viewpoint, the authors discuss the rationale and controversies surrounding this recommendation.

Objective: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 ( CCL3L1 ) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by β-chemokines is a feature of autoimmunity, and that the CCR5Δ32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). Methods: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. Results: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08–1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75–1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98–2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00–1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 ( CCR5 Δ 32 ). Conclusions: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5 Δ 32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

Background There have been few published studies in the UK that examined specifically the impact of ethnicity and age on Rheumatoid Arthritis (RA) outcomes, cross-sectional or longitudinal. From the available literature it seems uncertain whether differences in the clinical phenotype may result from the discrepancy in aetio-pathogenesis, or whether it is a consequence of environmental, cultural and socioeconomic factors. Objectives To study changes in Disease Activity Score (DAS28) and its components to identify severity of disease by ethnicity among patients with RA attending an outpatient clinic in a diverse inner city population. Methods All RA patients attending a large teaching hospital outpatient clinic between 2010 and 2014 were identified via a Rheumatology clinic database. The socio-demographic and clinical (DAS28 & HAQ) variables were obtained, including estimates of socioeconomic status using postcodes to obtain indices of multiple deprivation. Ethnicity data were self-reported. A mixed-effects linear model was used to examine the mean difference between ethnicity groups (White Caucasians versus Black patients) in clinical variables throughout follow up, including individual DAS28 components. Comparisons were adjusted for age, gender, disease duration and index of multiple deprivation. Results 815 RA patients were suitable for analysis: mean age was 62 years; 78% were female; a quarter of patients self-identified as Black (e.g. Afro-Caribbean, African). DAS28 was significantly higher in Black compared to White patients, even after adjustment. Analysis of the individual components revealed that this difference was driven by significantly higher ESR and patient global scores in Black patients. Tender and swollen joint counts were numerically higher, but the differences did not reach statistical significance in adjusted analyses. Disability levels were significantly higher in Black patients. Paradoxically the CRP was significantly lower in Black patients. Conclusions The disease pattern for Black patients with RA appear to be different in comparison to White Caucasians. Both subjective and objective measures were higher in Black patients. The observed differences may reflect different RA disease phenotypes or different treatment exposures. Significant disagreement was present between ESR and CRP in black patients. Ethnicity is a patient specific factor that clinicians need to take account of both when considering disease assessment and treatment pathways Disclosure of Interest J. Galloway: None declared, F. Ibrahim Employee of: King9s Collge London, A. Mian: None declared, N. Gullick: None declared, S. Steer: None declared, H. Lempp Grant/research support from: NIHR, Health Foundation, ARUK, EU, South London Membership Council, Employee of: King9s College London

Genetic factors are increasingly recognized to have an important contribution to the occurrence of both inflammatory and noninflammatory rheumatic disease. Although identifying the specific genetic mechanisms involved in the rheumatic diseases continues to present considerable challenges, the prospect of identifying individual gene action has been brought closer by a number of recent developments. These include newer approaches to phenotype definition, refinements in statistical tools for analysis, and the advent of newer technologies, including the use of microarrays. In this article, we review some of these developments together with the recent literature on the contribution of both broad and specific genetic factors to the spectrum of rheumatic disease. We also consider contemporary opinions on the potential impact of genetic discoveries to human health.

Introduction. It has been proposed that genetic susceptibility loci for rheumatoid arthritis (RA) may be shared with other autoimmuneuinflammatory diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome 16q12 has been associated with Crohn’s disease (CD) in several independent populations. CARD15 is an excellent functional and positional candidate gene for RA. Methods. Genomic DNA was obtained from 392 RA cases and 471 ethnically matched healthy controls. All samples were genotyped for two polymorphisms in CARD15, 1007fs and R702W, using 59 nuclease reporter assays. Allele frequencies were compared between cases and controls using the x 2 test. Estimated haplotype frequencies across the two mutations were determined using the EH program. Results. The allele frequency of the 1007fs variant in RA cases was 1.8% compared with 1.6% in normal controls (not significant). The frequency of the R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying both mutations was rare, with estimated frequency

Background Depression is highly prevalent in RA and is associated with increased mortality, disability and healthcare costs [1, 2]. There is limited evidence assessing the longitudinal impact of depression on RA outcomes, particularly objectively-reported clinical outcomes. Objectives To assess the impact of persistent depression on physical health outcomes over a 2-year follow-up period. Methods A secondary data analysis of a clinical trial (CARDERA) was performed [3]. Depression and physical health outcomes were measured at baseline and 6-montly intervals for 2-years. Depression was measured using the EQ-5D, and patients were categorised into 4 groups: 1) never depressed; 2) depressed at 50% of time-points; and 4) depressed at every time-point. Physical health outcomes were: Larsen score; tender joint count (TJC); swollen joint count (SJC); ESR; assessor and patient global assessments (AGA/PGA); HAQ; pain; and DAS-28. Results Data was available for 379 patients. Patients9 mean age was 54.1 (12.3), and 68.3% of the sample were female. In total, 25.9% were never depressed, 36.9% were depressed 50% of the time, and 15.8% were depressed at every time-point. Conclusions Increasing persistence of depression over time tends to be associated with poor physical health outcomes, with discordance between subjectively and objectively measured outcomes. These findings have significant implications: mental health should be measured and monitored throughout the course of treatment [4]; DAS-28 scores may be inflated in depressed patients, which needs to be considered when making treatment decisions. References Matcham F et al. The prevalence of depression in Rheumatoid Arthritis: A systematic review and meta-analysis. Rheumatology 2013; 52: 2136-48. Bruce T. Comorbid depression in rheumatoid arthritis: Pathophysiology and clinical implications. Current Psychiatry Reports 2008; 10: 258-64. Choy EHS et al. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 2008; 67: 656-63. Rayner L et al. Embedding integrated mental health assessment and management in general hospital settings: feasibility, acceptability and the prevalence of common mental disorder. Gen Hosp Psychiatr (in press), doi: 10.1016/j.genhosppsych.2013.12.004. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2878

Background Advances in imputation methods have enabled association studies of HLA protein amino acid polymorphisms and rheumatoid arthritis (RA) susceptibility. A recent meta-analysis of this region has attributed most of its association with seropositive RA to 5 amino acid positions [1]. Radiological progression in RA has a significant genetic component. Previous studies have linked shared-epitope alleles to radiological damage in RA; the association between HLA amino acid polymorphisms and radiological progression is unexplored. Objectives To evaluate the relationship between HLA amino acid polymorphisms and radiological progression (defined as the development of new erosions over 2 years) in early, active RA patients enrolled to a clinical trial. Methods The Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial randomised 467 patients to receive methotrexate with or without ciclosporin, corticosteroids or both treatments in a factorial-design. We evaluated 421 European ancestry patients with archived DNA (passing QC procedures) and radiological data available. Radiographs were evaluated 6-monthly (for 2 years) for the development of new erosions. Genotyping was performed on the ImmunoChip; HLA alleles and amino acid polymorphisms were imputed using SNP2HLA [2]. We evaluated 237 amino acid positions in 3 MHC class I and 5 MHC class II proteins and 255 HLA alleles for their association with new erosions. Association testing was performed using UNPHASED version 3.0.7, which utilises a standard retrospective likelihood model for a binary trait and allows the use of polymorphic markers [3]. A P -value threshold of 0.0002 was applied based on permutation testing. Ethical approval was obtained; all patients provided consent. Results One amino acid position, which was position 10 in HLA-DRβ1 ( P =0.0001) passed our pre-defined significance threshold for association with new erosions. Using glutamine as the reference amino acid, the OR for new erosions with tyrosine was 0.443 (95% CI 0.278-0.706). A similar trend was observed for HLA alleles; the strongest association was seen with HLA-DRB1 *04 ( P -value=0.0002), which encodes glutamine at position 10. The absence of *04 alleles provided an OR for new erosions of 0.513 (95% CI 0.360-0.730). Conclusions We demonstrate an association between amino acid polymorphisms at position 10 in the HLA-DRβ1 protein and the development of radiological erosions in early active RA. Unlike amino acid polymorphisms associating with RA susceptibility (located in binding grooves) this polymorphism influences β- and α-chain binding; it could therefore influence radiological damage through attenuating antigen presentation within the joint. Replication of our finding in other cohorts is required to confirm its validity. References Raychaudhuri S et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 2012 29; 44: 291-6. Jia X et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 2013; 8: e64683. Dudbridge F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008; 66: 87-98. Acknowledgements Arthritis Research UK (Grant Reference Number 19739 to ICS); National Institute for Health Research (NIHR) Biomedical Research Centre at Guy9s and St Thomas9 NHS Foundation Trust in partnership with King9s College London. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4069

Background Several studies have tested the hypothesis that RA susceptibility variants associate with radiological progression. Their findings are often not replicated; additionally they have examined only a proportion of risk loci and evaluated each locus separately, despite limited power. Two recent meta-analyses of genome-wide association studies have expanded the number of genetic loci and HLA amino acid polymorphisms associated with RA susceptibility [1, 2]. Our aim was to establish if these variants correlated with radiological progression in early active RA patients enrolled to a clinical trial. We evaluated their association both individually and cumulatively, using a weighted genetic risk score (wGRS) combining risk loci. Objectives To establish if genetic predictors of RA susceptibility also associate with radiological progression in early active RA. Methods We evaluated 421 RA patients previously enrolled to the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial. Hand/feet radiographs were read for modified Larsen scores every 6 months for 2 years. We evaluated the association of validated genetic risk variants (69 SNPs, 17 four-digit HLA-DRB1 alleles and polymorphisms in 6 HLA amino acid positions) with log-transformed Larsen scores over time using a linear mixed-effects model. Log e (Larsen score + 1) was the response variable. Time, treatment, age, disease duration, ACPA status, genotype and a genotype*time interaction, were the fixed-effects predictor variables. Genotype was coded additively. All β-estimates were back-transformed to the original Larsen scale. The genotype*time β provided information on the annual increase in Larsen score per risk allele copy relative to the reference genotype; P -values for this term provided information on the variant9s role in radiological progression. We assessed the association between a wGRS incorporating susceptibility SNPs and radiological progression by replacing the linear model9s genotype term with a wGRS. Ethical approval was obtained; all patients provided consent. Results Two SNPs, one HLA-DRB1 allele and two HLA-DRβ1 protein amino acid polymorphisms had P -values P =0.0680). Conclusions RA susceptibility loci did not have a clinically relevant association with radiological progression in European ancestry, early, active RA patients recruited to this trial. This suggests the genetic architectures of RA susceptibility and severity differ. References Okada Y et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2013; [Epub ahead of print]. Raychaudhuri S et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 2012;44:291-6. Acknowledgements Arthritis Research UK (Grant Reference Number 19739 to ICS); National Institute for Health Research (NIHR) Biomedical Research Centre at Guy9s and St Thomas9 NHS Foundation Trust in partnership with King9s College London. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5018

Background Prescribing patterns in Rheumatoid Arthritis have evolved over recent decades. There is now clear evidence that combination DMARDs and biologics can acheive better disease control. This is guided by the treat to target initiative aiming for remission in all patients. Objectives We have used observational data to determine changes in prescribing patterns since 1996. We set out to describe the % of patients with RA being treated with individual DMARDs, combination therapy, systemic steroids and biologics. Methods Our study included 1492 RA patients attending two rheumatology centres. They comprised four groups of clinic attenders attending between 1996 and 2013. We collected data on the use of DMARDs, systemic steroids and biologics. Data were also collected on the proportion of patients not receiving any immunosuppressive therapy. Results More patients received immunosuppressive treatment with 14% of all RA patients and 16% of intermediate disease activity group not on any treatment in 2012-13 compared with 32% and 23% in the 1996-97 cohort. Methotrexate remains the most frequently prescribed DMARD across all cohorts, however the more contemporaneous cohorts have higher exposure to hydroxychloroquine, sulfasalazine and leflunomide. Conversely, few patients ( The % of patients treated with combination therapy has increased, however almost half of patients remain on a single DMARD (46%). The proportion of patients treated with biologics has steadily increased from 0 to 1996-97, 4% in 2001-03 to 17% and 21% in the two later cohorts. Systemic steroid use has fluctuated over time, prescribed in 14% in 2012-13. Conclusions Increasing numbers of patients are being treated with immunosuppression. The choice of DMARD has changed from fewer patients being prescribed gold, penicillamine and azathioprine, to more patients being treated with methotrexate, hydroxychloroquine, sulfasalazine and leflunomide. Whilst the uptake of combination DMARD therapy and biologics has increased, approximately half of patients remain on a single DMARD only. This may be due to a number of reasons including physician choice, patient choice and drug intolerance. Further research is needed to explore this issue. There are still patients not on immunosuppression, suggesting that we are not treating to target, and not achieving tighter targeted control in all patients. Further research into why patients who have not achieved remission are not being treated with combination therapy is needed. The role of biologics in moderate disease activity patients to further try and achieve remission needs to be explored. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5399

Ian C. Scott, Jemma Walker, Jelmar Quist, Sarah Spain, Rachael Tan, Yuki Okada, Soumya Raychaudhuri, Sophia Steer, Andrew P. Cope and Cathryn M. Lewis Department of Rheumatology, King’s College London, London, Department of Medical and Molecular Genetics, King’s College London, London, UK, Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA, Department of Rheumatology, King’s College Hospital, London, UK

Background Socio-economic deprivation is known to be associated with an adverse prognosis in rheumatoid arthritis (RA); some of this may be due to differential interaction of individuals with their healthcare providers after symptom onset. Rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) status can precede clinical onset of RA by up to ten years and thus may provide a unique insight into factors affecting immunological events in the pre-clinical stage. In support of this, ACPA-positive and ACPA-negative RA have distinct genetic and environmental risk factors. Objectives To assess the association between area level socio-economic deprivation and the phenotype of RA, defined by RF and ACPA status, and to determine whether any observed association can be explained by smoking. Methods Logistic regression analysis of 6298 patients with RA, defined by American College of Rheumatology classification criteria modified for genetic studies. Analysis was stratified by cohort/recruitment centre. Socio-economic deprivation was measured using the Townsend index. Results Deprivation predicted RF but not ACPA positivity, independent of smoking. The odds ratios (OR) for trend across tertiles of deprivation, adjusted for smoking, gender, period of birth and cohort/recruitment centre, were: 1.14 (95% confidence interval (CI) 1.01 to 1.29) for RF, and 1.01 (95% CI 0.87 to 1.16) for ACPA. Even after adjusting for deprivation, smoking was strongly associated with ACPA positivity (OR 1.38, 95% CI 1.22 to 1.55). There was no evidence of any effect modification by the RA risk alleles ( HLA-DRB1 shared epitope and PTPN22 rs2476601) that are known to modify the effect of smoking on ACPA and RF positivity. Conclusions Amongst patients with RA, deprivation predicted RF positivity, but not ACPA positivity. The effect of deprivation did not appear to be explained by smoking. We avoided case-control response bias by performing a case-only analysis. Deprivation may be a marker for previously-unrecognised, potentially modifiable environmental influences on the immunological phenotype of RA. Furthermore, given the known associations of RF positivity with prognosis and response to treatment in RA, these findings have potential implications for resource allocation and healthcare delivery. Disclosure of Interest None Declared

Background Methotrexate (MTX) is the most commonly used disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Methotrexate pneumonitis (MP) is a potentially fatal hypersensitivity reaction with a mortality rate of ∼20%, the risk being maximal in the first year of treatment. The incidence of MP is higher in patients with pre-existing lung disease, particularly interstitial lung disease (ILD). Early identification of these patients provides the opportunity to offer an alternative agent. Prior to commencing MTX the current British Society for Rheumatology guidelines advise a screening chest radiograph (CXR). CXR has a low sensitivity for detecting ILD and it has been suggested that carbon monoxide transfer factor (TLCO) is a more sensitive marker. The guideline of the Rheumatology department at King’s College Hospital is to request a pulmonary function test (PFT) as well as a CXR prior to commencing MTX in all RA patients. If the TLCO is abnormal a high-resolution computerised tomography scan (HRCT) is considered. Objectives To investigate whether screening with PFT and CXR identifies more patients with ILD than screening with CXR alone. Methods 107 MTX-naive RA patients aged 21–86 who had previously had CXR and PFT were identified from the hospital database. Those patients with an abnormal TLCO (defined as ≤79% in non-smokers and ≤69% in smokers) who had undergone HRCT were included. Where ILD was identified on HRCT, the CXR was reviewed for abnormalities. Results Of the 107 patients, 44 with normal TLCO were excluded and a further 23 patients were excluded as they had not had HRCT. Of the 40 remaining patients, ILD was identified in 12 (see Table) of whom 6 (50%) had a normal CXR. 9 (75%) patients had early RA, defined as within 3 years of symptom onset. Of the 6 patients with abnormal CXR, 5 had TLCO Conclusions Our results show that the combination of CXR and PFT detects more patients with RA ILD compared to CXR alone, particularly in less advanced respiratory disease. In this cohort of RA patients undergoing pre-MTX screening we identified 12 patients with ILD, a prevalence of 11%. 50% of these patients would not have been identified by screening with CXR alone. MP is a rare but potentially fatal side-effect of MTX treatment. It is well recognized that prognosis is significantly worse in RA patients with ILD. Therefore we suggest early screening with PFT to identify these patients, allowing appropriately tailored management. References Disclosure of Interest : None Declared