TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.

Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4+ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (TH1) and TH17 cells, but not that of regulatory T cells. CD4+ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. METHODS: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. RESULTS: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs. CONCLUSIONS: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.

Prodromal symptoms of rheumatoid arthritis in a primary care database: variation by ethnicity and socioeconomic status.

OBJECTIVES: To assess whether prodromal symptoms of rheumatoid arthritis (RA), as recorded in the Clinical Practice Research Datalink Aurum (CPRD) database of English primary care records, differ by ethnicity and socioeconomic status. METHODS: A cross-sectional study to determine the coding of common symptoms (≥0.1% in the sample) in the 24 months preceding RA diagnosis in CPRD Aurum, recorded between January 1st 2004 to May 1st 2022. Eligible cases were adults with a code for RA diagnosis. For each symptom, a logistic regression was performed with the symptom as dependent variable, and ethnicity and socioeconomic status as independent variables. Results were adjusted for sex, age, BMI, and smoking status. White ethnicity and the highest socioeconomic quintile were comparators. RESULTS: In total, 70115 cases were eligible for inclusion, of which 66.4% female. Twenty-one symptoms were coded in > 0.1% of cases so were included in the analysis. Patients of South Asian ethnicity had higher frequency of codes for several symptoms, with the largest difference by odds ratio being muscle cramps (OR 1.71, 1.44-2.57) and shoulder pain (1.44, 1.25-1.66). Patients of Black ethnicity had higher prevalence of several codes including unintended weight loss (2.02, 1.25-3.28) and ankle pain (1.51, 1.02-2.23). Low socioeconomic status was associated with morning stiffness (1.74, 1.08-2.80) and falls (1.37, 2.03-1.82). CONCLUSION: There are significant differences in coded symptoms between demographic groups, which must be considered in clinical practice in diverse populations and to avoid algorithmic bias in prediction tools derived from routinely collected healthcare data.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

Differential effect of lactate on synovial fibroblast and macrophage effector functions.

Introduction: The synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters. Methods: Synovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets. Results: We show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion. Discussion: In this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.

Early onset of immune-mediated diseases in minority ethnic groups in the UK.

BACKGROUND: The prevalence of some immune-mediated diseases (IMDs) shows distinct differences between populations of different ethnicities. The aim of this study was to determine if the age at diagnosis of common IMDs also differed between different ethnic groups in the UK, suggestive of distinct influences of ethnicity on disease pathogenesis. METHODS: This was a population-based retrospective primary care study. Linear regression provided unadjusted and adjusted estimates of age at diagnosis for common IMDs within the following ethnic groups: White, South Asian, African-Caribbean and Mixed-race/Other. Potential disease risk confounders in the association between ethnicity and diagnosis age including sex, smoking, body mass index and social deprivation (Townsend quintiles) were adjusted for. The analysis was replicated using data from UK Biobank (UKB). RESULTS: After adjusting for risk confounders, we observed that individuals from South Asian, African-Caribbean and Mixed-race/Other ethnicities were diagnosed with IMDs at a significantly younger age than their White counterparts for almost all IMDs. The difference in the diagnosis age (ranging from 2 to 30 years earlier) varied for each disease and by ethnicity. For example, rheumatoid arthritis was diagnosed at age 49, 48 and 47 years in individuals of African-Caribbean, South Asian and Mixed-race/Other ethnicities respectively, compared to 56 years in White ethnicities. The earlier diagnosis of most IMDs observed was validated in UKB although with a smaller effect size. CONCLUSION: Individuals from non-White ethnic groups in the UK had an earlier age at diagnosis for several IMDs than White adults.

Acceptability of predictive testing for ischemic heart disease in those with a family history and the impact of results on behavioural intention and behaviour change: a systematic review.

BACKGROUND: Tests to predict the development of chronic diseases in those with a family history of the disease are becoming increasingly available and can identify those who may benefit most from preventive interventions. It is important to understand the acceptability of these predictive approaches to inform the development of tools to support decision making. Whilst data are lacking for many diseases, data are available for ischemic heart disease (IHD). Therefore, this study investigates the willingness of those with a family history of IHD to take a predictive test, and the effect of the test results on risk-related behaviours. METHOD: Medline, EMBASE, PsycINFO, LILACS and grey literature were searched. Primary research, including adult participants with a family history of IHD, and assessing a predictive test were included. Qualitative and quantitative outcomes measuring willingness to take a predictive test and the effect of test results on risk-related behaviours were also included. Data concerning study aims, participants, design, predictive test, intervention and findings were extracted. Study quality was assessed using the Standard Quality Assessment Criteria for Evaluating Research Papers from a Variety of Fields and a narrative synthesis undertaken. RESULTS: Five quantitative and two qualitative studies were included. These were conducted in the Netherlands (n = 1), Australia (n = 1), USA (n = 1) and the UK (n = 4). Methodological quality ranged from moderate to good. Three studies found that most relatives were willing to take a predictive test, reporting family history (n = 2) and general practitioner (GP) recommendation (n = 1) as determinants of interest. Studies assessing the effect of test results on behavioural intentions (n = 2) found increased intentions to engage in physical activity and smoking cessation, but not healthy eating in those at increased risk of developing IHD. In studies examining actual behaviour change (n = 2) most participants reported engaging in at least one preventive behaviour, particularly medication adherence. CONCLUSION: The results suggests that predictive approaches are acceptable to those with a family history of IHD and have a positive impact on health behaviours. Further studies are needed to provide a comprehensive understanding of predictive approaches in IHD and other chronic conditions.

Public perceptions of predictive testing for rheumatoid arthritis compared to breast cancer and early-onset Alzheimer's disease: a qualitative study.

BACKGROUND: There is increasing research focus on prediction and prevention of rheumatoid arthritis (RA). Information about risk of RA is increasingly available via direct-to-consumer testing. However, there is limited understanding of public perceptions around predictive testing for RA. This study explores public perceptions of predictive testing for RA in comparison to breast cancer (BC) and early-onset Alzheimer's disease (AD). METHODS: Four focus groups with 21 members of the public were conducted using hypothetical vignettes about predictive testing for each disease. Transcripts of focus group proceedings were analysed inductively using thematic analysis. RESULTS: Thematic analysis of the data produced three key themes: decision-making factors, consequences, and consumer needs. Factors suggested that might influence decision-making about predictive testing included family history, fear, and perceived severity and treatability of the illness. RA was perceived to be less severe and more treatable than BC/AD. Potential consequences of predictive testing across all diseases included lifestyle modification, planning for the future and discrimination by employers or insurers. Predictive testing for RA was perceived to have less potential for negative psychological consequences than other diseases. Participants highlighted that individuals undertaking predictive testing should be signposted to appropriate support services and receive information on the accuracy of predictive testing. It was suggested that strategies to mitigate concerns regarding communication and confidentiality of risk results are required. CONCLUSIONS: The findings of this study reflect public misunderstandings regarding RA that may impact the uptake of and responses to predictive testing, and key informational needs of individuals considering a predictive test. Predictive strategies should be accompanied by awareness-raising initiatives and informational resources.

Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study.

BACKGROUND: Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. METHODS: This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. DISCUSSION: This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. ETHICS AND DISSEMINATION: The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734496.

Relationship Between Inflammation and Metabolism in Patients With Newly Presenting Rheumatoid Arthritis.

Background: Systemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA. Methods: Serum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation. Results: Using PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP. Conclusions: This study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.

Spontaneously Resolving Joint Inflammation Is Characterised by Metabolic Agility of Fibroblast-Like Synoviocytes.

Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggesting that disease-associated metabolic changes are long-lasting. We term this phenomenon 'metabolic memory'. We identify changes in cell metabolism after acute TNFα stimulation across disease groups. When compared to FLS from patients with early rheumatoid arthritis, FLS from patients with resolving synovitis have significantly elevated mitochondrial respiratory capacity in the resting state, and less fragmented mitochondrial morphology after TNFα treatment. Our findings indicate the potential to restore cell metabotypes by modulating mitochondrial function at sites of inflammation, with implications for treatment of RA and related inflammatory conditions in which fibroblasts play a role.

BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study.

BACKGROUND: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. METHODS: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. DISCUSSION: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need. TRIAL REGISTRATION: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 .

The association between exposure to domestic abuse in women and the development of syndromes indicating central nervous system sensitization: A retrospective cohort study using UK primary care records.

BACKGROUND: Domestic abuse is a global public health issue. The association between the development of central sensitivity syndromes (CSS) and previous exposure to domestic abuse has been poorly understood particularly within European populations. METHODS: A retrospective cohort study using the 'The Health Improvement Network,' (UK primary care medical records) between 1st January 1995-31st December 2018. 22,604 adult women exposed to domestic abuse were age matched to 44,671 unexposed women. The average age at cohort entry was 36 years and the median follow-up was 2.5 years. The outcomes of interest were the development of a variety of syndromes which demonstrate central nervous system sensitization. Fibromyalgia, chronic fatigue syndrome and temporomandibular joint disorder outcomes have been reported previously. Outcomes were adjusted for the presence of mental ill health. RESULTS: During the study period, women exposed to domestic abuse experienced an increased risk of developing chronic lower back pain (adjusted incidence rate ratio [aIRR] 2.28; 95% CI 1.85-2.80), chronic headaches (aIRR 3.15; 95% CI 1.07-9.23), irritable bowel syndrome (aIRR 1.41; 95% CI 1.25-1.60) and restless legs syndrome (aIRR 1.89; 95% CI 1.44-2.48). However, no positive association was seen with the development of interstitial cystitis (aIRR 0.52; 95% CI 0.14-1.93), vulvodynia (aIRR 0.42; 95% CI 0.14-1.25) and myofascial pain syndrome (aIRR 1.01; 95% CI 0.28-3.61). CONCLUSION: This study demonstrates the need to consider a past history of domestic abuse in patients presenting with CSS; and also consider preventative approaches in mitigating the risk of developing CSS following exposure to domestic abuse. SIGNIFICANCE: Domestic abuse is a global public health issue, with a poorly understood relationship with the development of complex pain syndromes. Using a large UK primary care database, we were able to conduct the first global cohort study to explore this further. We found a strong pain morbidity burden associated with domestic abuse, suggesting the need for urgent public health intervention to not only prevent domestic abuse but also the associated negative pain consequences.

Intimate Partner Violence and the Risk of Developing Fibromyalgia and Chronic Fatigue Syndrome.

Intimate partner violence (IPV) is a global public health issue with a variety of ill health consequences associated with exposure. Due to the stimulation of chronic stress and inflammatory pathways, childhood abuse has been associated with the subsequent development of functional syndromes such as fibromyalgia and chronic fatigue syndrome (CFS). Although IPV in women appears to elicit similar biochemical responses, this association has not been tested thoroughly in IPV survivors. These functional syndromes are complex in etiology and any indication of their risk factors would benefit health care professionals managing this population. Therefore, we aimed to investigate the association between exposure to IPV with functional syndromes: fibromyalgia and CFS. We conducted a retrospective open cohort study using "The Heath Improvement Network" database between January 1, 1995 and December 1, 2017. A total of 18,547 women who were exposed to IPV were each matched by age to four controls who were not exposed (n = 74,188). The main outcome measures were the risk of developing fibromyalgia and CFS. These were presented as adjusted incidence rate ratios (aIRR) with 95% confidence intervals (CIs). We found that 97 women in the exposed group developed fibromyalgia (incidence rate [IR] = 1.63 per 1,000 person-years) compared to 239 women in the unexposed group (IR = 0.83 per 1,000 person-years). Following adjustment, this translated to an IRR of 1.73 (95% CI = [1.36, 2.22]). Similarly, 19 women developed CFS in the exposed group (IR = 0.32 per 1,000 person-years), compared to 53 in the unexposed group (0.18 per 1,000 person-years), which translates to an aIRR of 1.92 (95% CI = [1.11, 3.33]). Therefore, we have identified an association between a history of IPV in women and the development of these functional syndromes, which may provide more information to inform the biopsychosocial pathway precipitating the development of fibromyalgia and CFS.

Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids.

OBJECTIVES: The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11ß-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis. METHODS: Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11ß-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA. RESULTS: Global deletion of 11ß-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11ß-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11ß-HSD1. CONCLUSIONS: We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and amplification by 11ß-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.

The association between exposure to childhood maltreatment and the subsequent development of functional somatic and visceral pain syndromes.

BACKGROUND: Childhood maltreatment is a global public health issue linked to a vast mortality and morbidity burden. This study builds on current literature to explore the risk of developing central sensitivity syndromes (CSS) (consisting of somatic and visceral pain syndromes) subsequent to childhood maltreatment exposure. METHODS: A retrospective population based open cohort study using the UK primary care database, 'The Health Improvement Network,' between 1st January 1995-31st December 2018. 80,657 adult patients who had experienced childhood maltreatment or maltreatment related concerns (exposed patients) were matched to 161,314 unexposed patients by age and sex. Outcomes of interest were the development of CSS: either somatic (Fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, chronic lower back pain, chronic headache, myofascial pain syndrome and restless leg syndrome) or visceral (Interstitial cystitis, vulvodynia, chronic prostatitis and irritable bowel syndrome) in nature. Effect sizes are presented as adjusted incidence rate ratios (aIRR) with confidence intervals (CI). Models were adjusted for the following covariates at cohort entry: age, sex, deprivation, anxiety, depression and serious mental ill health. RESULTS: The average age at cohort entry was 23.4 years and the median follow was 2.2 years. There was an increased risk of developing fibromyalgia (aIRR 2.06; 95% CI 1.71-2.48), chronic fatigue syndrome (1.47; 1.08-2.00), chronic lower back pain (1.99; 1.68-2.35), restless leg syndrome (1.82; 1.41-2.35) and irritable bowel syndrome (1.15; 1.08-1.22) when compared to the unexposed group, whereas no statistical association was seen with the development of temporomandibular joint disorder (1.00; 0.88-1.13), chronic headache (1.04; 0.59-1.86), interstitial cystitis (1.19; 0.51-2.74), vulvodynia (0.65; 0.34-1.26), chronic prostatitis (0.34; 0.07-1.77) and myofascial pain syndrome (0.88; 0.36-2.14). Outcome numbers were low, most likely, due to the rarity of visceral conditions (aside from irritable bowel syndrome). The association between a history of childhood maltreatment and CSS were mainly observed in somatic CSS. INTERPRETATION: The debilitating effects of CSS carry a substantial physical, psychological and economic burden to both the individuals who are diagnosed with them and the health services who serve them. Primary prevention approaches targeting childhood maltreatment as well as secondary preventative approaches should be considered to minimise the associated burden of CSS.

Cardiovascular risk factors and outcomes in early rheumatoid arthritis: a population-based study.

OBJECTIVE: To assess the burden of cardiovascular disease (CVD) at and prior to diagnosis in people with early rheumatoid arthritis (RA) and subsequent CVD in these patients. METHODS: A retrospective case-control study using a large English primary care database. People with RA (n=6591) diagnosed between 2004 and 2016 (inclusive) were identified using a validated algorithm, matched 1:1 by age and gender to those without RA (n=6591) and followed for a median of 5.4 years. We assessed differences in CVD at, before and after diagnosis, and the impact of traditional and RA-related risk factors (C reactive protein, RA-related autoantibodies and medication use) on incident CVD (a composite of myocardial infarction (MI), stroke or heart failure). RESULTS: RA cases and their matched controls were both of mean age 58.7 (SD 15.5) at cohort entry, and 67.5% were female. Some CVD risk factors were more common at RA diagnosis including smoking and diabetes; however, total and low-density lipoprotein cholesterol were lower in patients with RA. CVD was more common in RA at cohort entry; stroke (3.9% vs 2.7%, p<0.001), heart failure (1.6% vs 1.0%, p=0.001), and non-significantly MI (3.1% vs 2.8%, p=0.092). Excess CVD developed in the 5 years preceding diagnosis. After adjustment for traditional and RA-related risk factors, RA was associated with greater risk of post-diagnosis CVD (HR 1.33, 95% CI 1.07 to 1.65, p=0.010). CONCLUSIONS: An excess of stroke and heart failure occurs before diagnosis of RA. There is excess risk for further cardiovascular events after diagnosis, which is not explained by differences in traditional CVD or RA-related risk factors at diagnosis.

I Would Never Take Preventive Medication! Perspectives and Information Needs of People Who Underwent Predictive Tests for Rheumatoid Arthritis.

OBJECTIVE: Little is known about the experiences, values, and needs of people without arthritis who undergo predictive biomarker testing for the development of rheumatoid arthritis (RA). Our study aimed to explore the perspectives of these individuals and describe their information needs. METHODS: A qualitative, multicenter interview study with a thematic analysis was conducted in Austria, Germany and the UK. Individuals were interviewed who underwent predictive biomarker testing for RA and had a positive test result but no diagnosis of any inflammatory joint disease. Participants included patients with arthralgia and asymptomatic individuals. Information and education needs were developed from the qualitative codes and themes using the Arthritis Educational Needs Assessment Tool as a frame of reference. RESULTS: Thematic saturation was reached in 34 individuals (76% female, 24 [71%] with arthralgia, and 10 [29%] asymptomatic individuals). Thirty-seven codes were summarized into 4 themes: 1) decision-making around whether to undergo initial predictive testing, 2) willingness to consider further predictive tests, and/or 3) preventive interventions, including medication, and 4) varying reactions after receiving a positive test result. Individuals with arthralgia were more likely to be willing to take preventive action, undergo further testing, and experience psychological distress than asymptomatic individuals. All participants expressed the need for tailored, patient-understandable information. CONCLUSION: Individuals at risk of RA are currently the subjects of research aimed at developing better predictive strategies and preventive approaches. Their perceptions and needs should be addressed to inform the future development of interventions combined with education.

Prognostic value of comorbidity indices and lung diseases in early rheumatoid arthritis: a UK population-based study.

OBJECTIVES: We assessed comorbidity burden in people with RA at diagnosis and early disease (3 years) and its association with early mortality and joint destruction. The association between lung disease and mortality in RA is not well studied; we also explored this relationship. METHODS: From a contemporary UK-based population (n = 1, 475 762) we identified a cohort with incident RA (n = 6591). The prevalence of comorbidities at diagnosis of RA and at 3 years was compared with age- and gender-matched controls (n = 6591). In individuals with RA we assessed the prognostic value of the Charlson Comorbidity Index and Rheumatic Disease Comorbidity Index calculated at diagnosis for all-cause mortality and joint destruction (with joint surgery as a surrogate marker). We separately evaluated the association between individual lung diseases [chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease] and mortality. RESULTS: Respiratory disease, cardiovascular disease, stroke, diabetes, previous fracture and depression were more common (P < 0.05) in patients with RA at diagnosis than controls. Comorbidity (assessed using RDCI) was associated with all-cause mortality in RA [adjusted hazard ratio (HR) 1.26, 95% CI 1.00-1.60]. There was no association with joint destruction. COPD, but not asthma, was associated with mortality (COPD HR 2.84, 95% CI 1.13-7.12). CONCLUSION: There is an excess burden of comorbidity at diagnosis of RA including COPD, asthma and interstitial lung disease. COPD is a major predictor of early mortality in early RA. Early assessment of comorbidity including lung disease should form part of the routine management of RA patients.

Preferences of Patients and At-risk Individuals for Preventive Approaches to Rheumatoid Arthritis.

Effective treatments for rheumatoid arthritis (RA) are available and can lead to remission for some patients, but most patients remain on potentially toxic and expensive medications in the long term. Interest is increasingly turning to the disease phases preceding the development of RA that represent opportunities for preventive interventions. At-risk target populations include individuals with genetic and environmental risk factors, those who have developed systemic autoimmunity, and those who have developed clinically suspect symptoms (eg, arthralgias without synovitis, or an early arthritis). Ongoing prospective studies will inform the development of increasingly accurate predictive tools to identify individuals at risk of developing RA. Furthermore, a range of preventive approaches has been suggested, including lifestyle modification (eg, smoking cessation) and pharmacologic interventions (eg, hydroxychloroquine, methotrexate, abatacept, rituximab) that are currently the subject of randomized controlled trials. As prediction and prevention of RA evolve, it is increasingly likely that individuals at risk (including asymptomatic individuals) may be faced with complex decisions about whether to accept assessment of their risk status or to take a preventive intervention associated with risk of serious adverse events and uncertain benefit. Acceptance of preventive medication in other contexts can be low. For example, <25% of women at high risk of breast cancer are willing to take preventive hormonal treatments. Actual uptake is lower still. Patients' beliefs and preferences predict treatment uptake and adherence. Before the dream of preventing RA can become reality, health care providers need to understand the perspectives of individuals in the target population and to identify barriers and facilitators for this approach. This commentary reviews what is currently known about the perspectives of patients and individuals at risk about predictive and preventive approaches for RA and identifies gaps to be addressed to inform the development of efficient preventive strategies.