Incidence of Uveitis in Patients With Axial Spondylarthritis Treated With Biologics or Targeted Synthetics: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Anterior uveitis is a common extra-articular manifestation of axial spondyloarthritis (AxSpA). We set to evaluate the risk of anterior uveitis (AU) with biologics and synthetic disease-modifying drugs in AxSpA. METHODS: We conducted a systematic review and meta-analysis to identify phase II/III double-blinded randomized controlled trials of anti-tumor necrosis factor (TNF) monoclonal antibodies (mAb), anti-interleukin-17 (anti-IL-17), and Janus kinase inhibitors (JAKi) in AxSpA. Patient-exposure years (PEY) were calculated using the per-protocol approach. Incidence rate (IR) of AU/100 person-years were calculated by treatment group using the random effects approach. Network meta-analysis (NMA) was used to estimate risk of AU in treatment groups, expressed as IR ratios (IRRs). Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: Forty-four trials were included: 17 anti-TNF mAb (1,004 PEY), 9 etanercept (180 PEY), 13 anti-IL-17 (1,834 PEY), and 6 JAKi (331 PEY). The IR of AU were as follows for anti-TNF mAb: 4.1, 95% confidence interval (CI) 0-8.5; etanercept: 5.4, 95% CI 0-16.0; anti-IL-17: 2.8, 95% CI 1.6-4.1; JAKi: 1.5, 95% CI 0.0-3.0; and placebo: 10.8, 95% CI 7.4-14.1. In NMA, IRRs of treatments compared with placebo were as follows for anti-TNF mAb: 0.32, 95% CI 0.10-1.04; etanercept 0.42, 95% CI 0.08-2.38; anti-IL-17: 0.43, 95% CI 0.19-0.98; and JAKi: 0.32, 95% CI 0.06-1.67. Comparisons between anti-TNF mAb, anti-IL-17, and JAKi did not demonstrate any significant difference in AU risk. Using the surface under the cumulative ranking curve approach to rank AU risk, anti-TNF mAbs were associated with the lowest risk followed by JAKi, anti-IL-17, and etanercept. All treatments were ranked superior to placebo. CONCLUSION: Anti-TNF mAbs, JAKi, and anti-IL-17 appear protective against AU events in individuals with AxSpA, with no significant differences in risk of AU between treatments.

Exploring the emotional impact of axial Spondyloarthritis: a systematic review and thematic synthesis of qualitative studies and a review of social media.

BACKGROUND: The psychological burden in people with inflammatory arthritis is substantial, yet little is known about the disease-related affect experienced by individuals with axial Spondyloarthritis (axial SpA). The aim of this study was to conduct a qualitative evidence synthesis and a review of social media to explore the emotional impact of living with axial SpA. METHODS: We searched nine databases for studies reporting qualitative data about participants' emotional experience of living with axial SpA. In addition, we searched social media platforms for posts from people with axial SpA based in the UK that offered insights into emotional responses to living with the condition. We employed a thematic approach to synthesise the data. RESULTS: We included 27 studies (1314 participants; 72% men) in our qualitative evidence synthesis and developed seven descriptive themes from the data: 1) delayed diagnosis: a barrier to emotional wellbeing; 2) disruptive symptoms: a source of mood swings; 3) work disability: a loss of self-esteem; 4) obstacles in interpersonal relationships: a trigger of distress; 5) taking up exercise: personal pride or unwelcomed reminders; 6) anti-TNF therapy: hope reignited despite concerns and 7) a journey of acceptance: worry mixed with hope. Posts extracted from social media fora (537; 48% from women) for the most part supported the seven themes. One additional theme-COVID-19, uncertainty and anxiety during the pandemic, was developed, reflecting common emotions expressed during the UK's first wave of the coronavirus pandemic. CONCLUSION: This study highlights a preponderance of negative affect experienced by people living with axial SpA, conditioned through existing and anticipated symptoms, failed expectations, and lost sense of self. Given the bidirectional relationships between negative emotions and inflammation, negative emotions and perceptions of pain, and the influence of affect in self-care behaviours, this finding has important implications for treatment and management of people with axial SpA.

Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases.

BACKGROUND: 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. METHODS: 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. RESULTS: 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<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS. CONCLUSIONS: Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.

The Impact of Targeted Rheumatoid Arthritis Pharmacologic Treatment on Mental Health: A Systematic Review and Network Meta-Analysis.

Rheumatoid arthritis (RA) pharmacotherapy may impact mental health outcomes by improving pain and stiffness, potentially by targeting inflammatory processes common to RA and depression. The objectives of this review were to ascertain the frequency of mental health assessments in RA pharmacotherapy trials, quantify the efficacy of RA pharmacotherapy for mental health outcomes, and explore the clinical and demographic factors related to mental health outcomes. Effective pharmacotherapy alone is unlikely to substantially improve mental health outcomes in most patients with RA. Integrated mental health care provided within routine clinical practice is essential to optimize mental and physical health outcomes.

The relationship between depression and biologic treatment response in rheumatoid arthritis: An analysis of the British Society for Rheumatology Biologics Register.

Objective: To investigate the relationship between depressive symptoms and treatment response and disease activity in RA over a 1-year follow-up. Methods: Data from the British Society for Rheumatology Biologics Register were used, representing 18 421 RA patients receiving biologic treatment. Depressive symptoms were identified through one of three assessments: reporting a history of depression, the Medical Outcomes Survey 36-item Short Form or the EuroQol five-dimension scale. Logistic regression analyses examined the relationship between baseline depressive symptoms and odds of good treatment response by 1 year. Multilevel models addressed the association between baseline depressive symptoms and disease activity outcomes over 1-year follow-up, adjusting for age, gender, disease duration, comorbidities and baseline disease activity and physical disability. Results: Depression symptoms at biologic treatment initiation were associated with 20-40% reduced odds of achieving a good treatment response at 1 year. Depressive symptoms at baseline also associated with reduced improvement in disease activity over the course of follow-up. Patients with a history of depression or reporting symptoms of depression according to the EuroQol five-dimension scale showed reduced improvement in tender and swollen joints, patient global assessment and ESR over 1-year follow-up. Patients with depression symptoms according to the 36-item Short Form showed reduced improvement in tender and swollen joints, but not ESR or patient global assessment. Conclusion: Experiencing symptoms of depression at the start of biologics treatment may reduce the odds of achieving a good treatment response, and reduce improvement in disease activity over time. Depression should be managed as part of routine clinical care to optimize treatment outcomes.

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case-control study.

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.

The Relationship Between Mental Health, Disease Severity, and Genetic Risk for Depression in Early Rheumatoid Arthritis.

OBJECTIVE: Reduced mental health (MH) is prevalent in rheumatoid arthritis (RA). Although longitudinal studies are limited, there is evidence that depression is associated with worse disease outcomes. We evaluated reciprocal relationships between MH, RA severity, and genetic risks for depression for 2 years in a well-characterized cohort of RA patients. METHODS: We evaluated 520 early RA patients previously enrolled to two clinical trials. MH was measured using the short form-36 MH domain and mental component summary scores (MCS). MCS/MH associations over 2 years with disease activity (disease activity score on a 28-joint count), disability (health assessment questionnaire), pain visual analog scale scores, and a weighted genetic risk score for depression were tested using linear mixed-effects and regression models. RESULTS: Poorer MH was associated with worse RA outcomes. Lower MCS scores (indicating worse MH) were seen in patients with a greater genetic risk for depression (weighted genetic risk score: coefficient = -1.21, p = .013). Lower baseline MCS was associated with lower 2-year improvements in disease activity score on a 28-joint count (coefficient = -0.02, p < .001), pain (coefficient = -0.33, p < .001), and health assessment questionnaire (coefficient = -0.01, p = .006). Baseline MCS was associated with changes in the swollen joint count (coefficient = -0.09, p < .001) and patient global assessment (coefficient = -0.28, p < .001) but not the tender joint count (p = .983) and erythrocyte sedimentation rate (p = .973). Only baseline pain visual analog scale (coefficient = -0.07, p = .002) was associated with 2-year changes in MCS. CONCLUSIONS: Reduced baseline MH was associated with lower improvements in disease activity, disability, and pain for 2 years, supporting current national guidelines recommending screening for depression in RA. Pain had a bidirectional relationship with MH. Depression genetic risk had a significant association with MH.

Patient involvement in rheumatology outpatient service design and delivery: a case study.

BACKGROUND: Patient involvement is increasingly recognized as important within the UK National Health Service to ensure that services delivered are relevant to users' needs. Organizations are encouraged to work with service users to achieve excellence in care. Patient education can improve health outcomes and reduce health-care costs. Mobile technologies could play a vital role in this. AIM: Patient-centred development of innovative strategies to improve the experience of rheumatology outpatients. CASE STUDY: The Group Rheumatology Initiative Involving Patients (GRIIP) project was set up in 2013 as a joint venture between patients, clinicians, academics and management at a London hospital. The project saw (i) the formation of an independent patient group which provided suggestions for service improvement - outcomes included clearer signs in the outpatient waiting area, extended phlebotomy opening hours and better access to podiatry; (ii) a rolling patient educational evening programme initiated in 2014 with topics chosen by patient experts - feedback has been positive and attendance continues to grow; and (iii) a mobile application (app) co-designed with patients launched in 2015 which provides relevant information for outpatient clinic attendees and data capture for clinicians - downloads have steadily increased as users adopt this new technology. CONCLUSION: Patients can effectively contribute to service improvement provided they are supported, respected as equals, and the organization is willing to undergo a cultural change.

Usefulness of the SF-36 Health Survey in screening for depressive and anxiety disorders in rheumatoid arthritis.

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.

Changing clinical patterns in rheumatoid arthritis management over two decades: sequential observational studies.

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 < 2.6) increased (8% to 28%). In contrast HAQ scores were unchanged (1.30 to 1.32) and correlations between DAS28 and HAQ weakened (Spearman's rho fell from 0.56 to 0.44). 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.

Symptoms of depression and anxiety predict treatment response and long-term physical health outcomes in rheumatoid arthritis: secondary analysis of a randomized controlled trial.

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-5D(TM)) 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.

Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?

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-DRß1 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.

The impact of rheumatoid arthritis on quality-of-life assessed using the SF-36: a systematic review and meta-analysis.

OBJECTIVE: The 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. METHODS: MEDLINE 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. RESULTS: In 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. CONCLUSIONS: RA 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.

Novel rheumatoid arthritis susceptibility locus at 22q12 identified in an extended UK genome-wide association study.

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.

Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-analysis of genome-wide data.

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.

Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking.

The improved characterisation of risk factors for rheumatoid arthritis (RA) suggests they could be combined to identify individuals at increased disease risks in whom preventive strategies may be evaluated. We aimed to develop an RA prediction model capable of generating clinically relevant predictive data and to determine if it better predicted younger onset RA (YORA). Our novel modelling approach combined odds ratios for 15 four-digit/10 two-digit HLA-DRB1 alleles, 31 single nucleotide polymorphisms (SNPs) and ever-smoking status in males to determine risk using computer simulation and confidence interval based risk categorisation. Only males were evaluated in our models incorporating smoking as ever-smoking is a significant risk factor for RA in men but not women. We developed multiple models to evaluate each risk factor's impact on prediction. Each model's ability to discriminate anti-citrullinated protein antibody (ACPA)-positive RA from controls was evaluated in two cohorts: Wellcome Trust Case Control Consortium (WTCCC: 1,516 cases; 1,647 controls); UK RA Genetics Group Consortium (UKRAGG: 2,623 cases; 1,500 controls). HLA and smoking provided strongest prediction with good discrimination evidenced by an HLA-smoking model area under the curve (AUC) value of 0.813 in both WTCCC and UKRAGG. SNPs provided minimal prediction (AUC 0.660 WTCCC/0.617 UKRAGG). Whilst high individual risks were identified, with some cases having estimated lifetime risks of 86%, only a minority overall had substantially increased odds for RA. High risks from the HLA model were associated with YORA (P<0.0001); ever-smoking associated with older onset disease. This latter finding suggests smoking's impact on RA risk manifests later in life. Our modelling demonstrates that combining risk factors provides clinically informative RA prediction; additionally HLA and smoking status can be used to predict the risk of younger and older onset RA, respectively.

The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis.

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.