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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

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

We thank Dr Zembrzuska for her letter relating to our systematic review and network meta‐analysis describing the impact of targeted pharmacological treatments on mental health outcomes in rheumatoid arthritis (RA) [1]. She highlights clearly the disparity in approach towards managing physical versus mental comorbidities in rheumatological practice. Approximately one in four people with RA will also have symptoms of depression [2] and there has been extensive recent research conducted by us here at King's College London, and by colleagues worldwide emphasising the impact common mental disorders such as symptoms of depression and anxiety may have on long‐term physical health outcomes and treatment response in RA [3‐6].

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.

Background Adolescents and young adults (AYA) form one sixth of the world’s population and account for 6% of the world’s global burden of disease. Those with chronic illness are particularly vulnerable. Globally, significant improvements in healthcare related morbidity and mortality have been seen, but not within the 10–24 year old group. Adolescence is a rapidly changing, formative phase of human development; opportunities exist to impact this through restructing care pathways and patient empowerment. Objectives Establish awareness of current national guidance and identify unmet needs in existing rheumatology AYA systems. Methods Interested parties from South East England (South London, Kent, Surrey and Sussex) formed a multi-disciplinary, patient based, co-design initiative (RAYA collaborative) which included representatives from primary/secondary/tertiary care, allied health professionals and a youth worker/patient from the charity sector. Our discussions and an anonymous survey to hospitals in the region, formed the basis of a qualitative and quantitative analysis, which helped gain a holistic insight into the challenges and opportunities in delivering AYA care in our region. Results 15/20 centres, covering an 8 million population, responded; 4 tertiary care hospitals, 11 district general hospitals with 32 responses (19 consultants, 13 senior registrars). 31 (97%) of responders felt that AYA cohort (16–25 years old) required an approach different to that of older adults. 25 (78%) felt there was a need for dedicated AYA services. 23 (72%) and 17 (53%) were aware of UK national guidelinesCQC 2014/NICE NG43 2016 respectively) for transitional/integrated and coordinated care. Barriers to developing dedicated AYA services (% of responders): Not a priority for NHS managers,31 other clinical priorities,31 insufficient patient numbers,22 not cost effective,19 unlikely to be commissioned,19 more research required,13 cohort by diagnosis,13 other ways to deliver care,13 only focus on transitioning patients from paediatrics13 Responders would like assistance in future care delivery through: Clinical toolkit: 63% n=20, Service commissioning toolkit: 43% n=14, Training: 43% n=14, Workshops: 47% n=15. Potential low cost/cost neutral approaches to systems change, cultural change, education and sharing of resource were discussed (see image). Conclusions Improving outcomes for AYA patients through delivering age appropriate care and self advocacy has driven global strategy and guidelines. Our survey identifies that the majority of rheumatologists agree with this, however there is room for improvement regarding awareness and implementation of current guidance. Financial constraints and whole population healthcare delivery has limited change. A systematic, unified approach within regions may help to effect change. There is a demand for the development of clinical and commissioning toolkits and training/workshops to help facilitate this. Reference [1] Global Accelerated Act on for the Health of Adolescents WHO2017. Disclosure of Interest None declared

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: To assess the feasibility and acceptability of routine web-based screening in general hospital settings, and describe the level of common mental disorder. Method: A service development platform to integrate mental and physical healthcare was implemented in six specialties (rheumatology, limb reconstruction, hepatitis C, psoriasis, adult congenital heart disease (ACHD), chronic pain) across three general hospitals in London, UK. Under service conditions, patients completed a web-based questionnaire comprising mental and physical patient-reported outcome measures, whilst waiting for their appointment. Feasibility was quantified as the proportion of patients who completed the questionnaire. Acceptability was quantified as the proportion of patients declining screening, and the proportion requiring assistance completing the questionnaire. The prevalence of probable depression and anxiety was expressed as the percentage of cases determined by the Patient Health Questionnaire-9 and Generalised Anxiety Disorder Questionnaire-7. Results: The proportion of patients screened varied widely across specialties (40.1-98.2%). The decline rate was low (0.6-9.7%) and the minority required assistance (11.7-40.4%). The prevalence of probable depression ranged from 60.9% in chronic pain to 6.6% in ACHD. The prevalence of probable anxiety ranged from 25.1% in rheumatology to 11.4% in ACHD. Conclusion: Web-based screening is acceptable to patients and can be effectively embedded in routine practice. General hospital patients are at increased risk of common mental disorder, and routine screening may help identify need, inform care and monitor outcomes.

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.

Introduction: The K-BILD is a validated HRQOL questionnaire. We previously reported the MID is 8 units. Item responses are now transformed to logits rather than using raw responses, as this is potentially a more linear scale (Patel A, JCE 2015;68;1019). The aim of this study was to re-evaluate the K-BILD MID using the logit scale. Methods: 57 patients with ILD (17-IPF) completed the K-BILD on 2 occasions. At the second visit patients also completed a Global rating of change of health status questionnaire (GRCQ). The MID was calculated as the mean of 4 different methods (anchors): GRCQ, 7-12% change in FVC, 1 SEM and effect size (ES) of 0.3. Results: The mean(SD) K-BILD Total score for all patients was 55.3(15.6). 36 patients reported a change in their condition on the GRCQ. There was a significant change in K-BILD score in patients reporting a change in GRCQ; mean(SD) 57.0(13.6) vs. 50.0(9.7); mean diff 7.0; 95% CI 3.0 to 11.0; p

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.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

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.

Objectives. To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals. Methods. A case–control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture. Results. European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 −7). HLA haplotype ORs in European and African ancestry individuals were highly correlated (r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 −4). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 −4) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 −5) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 −3). Conclusion. Gene–environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.

Connective tissue disease (CTD) and sickle cell disease (SCD) are diverse group of disorders; however, both of these diseases are characterized by underlying chronic inflammation. CTD is perceived to have a higher incidence and to affect the disease severity in SCD. Objectives: We seek to describe prevalence of autoimmunity and CTD and itsimpact on SCD disease severity as this is not well described in the literature. Methods: We retrospectively reviewed the medical records of 722 patients with SCD, seen over an 11 year period followed at a tertiary care hospital in London, UK. During the last 2 years of the study, number of hospitalizations and length of hospital stay were compared in patients with SCD with and without CTD. Results: In the study cohort, hemoglobin SS was the most common genotype (n = 451; 62%) and 411 (57%) were female. Twenty-three patients (3.1% had documented evidence of CTD, with rheumatoid arthritis (n = 14; 2%) and systemic lupus erythematosus (n = 2; 0.3%) being the most common. Antinuclear antibody was present in 108 (15%) of the patients and anti-smooth muscle antibody was present in 60 (8%). The mean number of hospitalizations (1.9 ± 2.7 vs. 1.5 ± 2.7) and mean length of hospital stay (6 days ± 4.1 vs. 7 days ± 11.4) were not different between those with or without autoimmunity and/or CTD. Avascular necrosis was the most common non-CTD musculoskeletal complication, affecting 72 (10%) patients. Conclusion: Our study suggests that positive autoimmune serology and CTD were more common in SCD compared to non-SCD population of similar ethnic background; however, presence of CTD does not appear to affect the SCD severity. The high frequency of CTD and overlapping of clinical symptoms suggest a need for diagnostic vigilance in diagnosing CTD in patients with SCD.

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.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

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.

A single-nucleotide polymorphism (C1858T) causing an amino acid substitution (R620W) in the lymphoid protein tyrosine phosphatase gene PTPN22 has been implicated in type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, juvenile idiopathic arthritis and Hashimoto's thyroiditis, thus revealing a general role for this gene in autoimmune disease. We investigated the association of the C1858T variant in an additional autoimmune disease population by performing a case-control study of 514 British individuals with inflammatory bowel disease (IBD) [294 with Crohn's disease (CD) and 220 with ulcerative colitis (UC)] and 374 normal controls. No significant differences in genotype or allele frequencies were observed between IBD, CD or UC and controls, indicating that PTPN22 does not influence risk of IBD.