The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

Notch signalling drives synovial fibroblast identity and arthritis pathology.

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3-5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

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.

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.

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.

Preferences for preventive treatments for rheumatoid arthritis: discrete choice survey in the UK, Germany and Romania.

OBJECTIVE: To quantify preferences for preventive therapies for rheumatoid arthritis (RA) across three countries. METHODS: A web-based survey including a discrete choice experiment was administered to adults recruited via survey panels in the UK, Germany and Romania. Participants were asked to assume they were experiencing arthralgia and had a 60% chance of developing RA in the next 2 years and completed 15 choices between no treatment and two hypothetical preventive treatments. Treatments were defined by six attributes (effectiveness, risks and frequency/route of administration) with varying levels. Participants also completed a choice task with fixed profiles reflecting subjective estimates of candidate preventive treatments. Latent class models (LCMs) were conducted and the relative importance of attributes, benefit-risk trade-offs and predicted treatment uptake was subsequently calculated. RESULTS: Completed surveys from 2959 participants were included in the analysis. Most participants preferred treatment over no treatment and valued treatment effectiveness to reduce risk more than other attributes. A five-class LCM best fitted the data. Country, perceived risk of RA, health literacy and numeracy predicted class membership probability. Overall, the maximum acceptable risk for a 40% reduction in the chance of getting RA (60% to 20%) was 21.7%, 19.1% and 2.2% for mild side effects, serious infection and serious side effects, respectively. Predicted uptake of profiles reflecting candidate prevention therapies differed across classes. CONCLUSION: Effective preventive pharmacological treatments for RA were acceptable to most participants. The relative importance of treatment attributes and likely uptake of fixed treatment profiles were predicted by participant characteristics.

The value of ultrasound-defined tenosynovitis and synovitis in the prediction of persistent arthritis.

OBJECTIVES: The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis. METHODS: One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months' follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables. RESULTS: At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis [odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002] provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis. CONCLUSION: US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development.

Outcomes of periodontal therapy in rheumatoid arthritis: The OPERA feasibility randomized trial.

AIM: Periodontitis is independently associated with rheumatoid arthritis (RA); however, there is limited data on whether periodontal treatment improves overall RA disease activity. We conducted a pilot feasibility randomized controlled clinical trial to test whether intensive periodontal therapy reduces RA disease activity in patients with active RA and periodontitis. MATERIALS AND METHODS: The following inclusion criteria were applied: patients with RA and periodontitis, aged 18+, stable on treatment with disease-modifying anti-rheumatic drugs for ≥3 months, disease activity score (DAS28) ≥3.2, and DAS28 >5.1 only if patient unwilling to take biologics. Participants meeting the inclusion criteria were randomized to immediate intensive periodontal therapy or to delayed therapy (control group) administered by a dental hygienist in a secondary care setting. Data were collected at baseline and at 3 and 6 months of follow-up. Participants randomized to the control group (delayed therapy) received the standard of care for the duration of the trial, including oral hygiene instructions delivered by a dental hygienist, and the same periodontal therapy as the intervention group after study completion (i.e., 6 months after randomization). The periodontal inflammation surface area was calculated using clinical attachment loss (CAL), periodontal probing pocket depth, and bleeding on probing. Cumulative probing depth was also measured. We examined the effect of periodontal therapy on periodontal outcomes and on clinical markers of disease activity in RA, as measured by the DAS28-C-reactive protein score as well as musculo-skeletal ultrasound grey scale and power Doppler scores. RESULTS: A total of 649 patients with RA were invited to participate in the study. Of these, 296 (46%) consented to participate in the screening visit. A sample of 201 patients was assessed for eligibility, of whom 41 (20%) did not meet the RA inclusion criteria and 100 (50%) did not meet the periodontal disease criteria. Among the 60 (30%) eligible participants, 30 were randomized to immediate periodontal therapy and 30 were allocated to the control group. The loss to follow-up was 18% at the end of the trial. There were no major differences with regard to baseline characteristics between the groups. Periodontal therapy was associated with reduced periodontal inflamed surface area, cumulative probing depths, RA disease activity scores, and ultrasound scores over the course of the trial. There was no change in CAL. CONCLUSIONS: Overall, the trial was feasible and acceptable to the study participants. Recruitment to and satisfactory retention in a randomized controlled trial on the effect of periodontal treatment on RA patients is possible, albeit challenging. In this feasibility study of patients with RA and periodontitis, periodontal treatment resulted in significant improvements in periodontal disease outcomes and overall RA disease activity, although complete resolution of periodontal inflammation was difficult to achieve in some cases.

Delay in diagnosis of rheumatoid arthritis: reasons and trends over a decade.

INTRODUCTION: Delay in diagnosis and treatment initiation often lead to poorer outcomes in rheumatoid arthritis (RA). Most of the data on delay in diagnosis and management are from western population with no data from India. Additionally, with improved health care services, whether the delay has changed over years is not known. In this longitudinal observational study, we investigated delay to diagnosis and disease-modifying antirheumatic drugs (DMARDs) initiation over past 9 years. METHODS: Patients aged ≥ 18 years having RA fulfilling 2010 ACR/EULAR criteria were enrolled from January to June in years 2012, 2017 and 2021. Diagnoses received before presenting to clinic, socioeconomic status, educational level and other demographic variables were recorded. RESULTS: Each year, 323 patients (mean age 49.5-52.01 years) were enrolled. There was a significant reduction in delay in diagnosis from a median (IQR) of 36 (12-84, range 1-288) months in 2012 to 12 (4-36, range 1-180) months in 2017 and 10 (5-24, range 1-120) months) in 2021 (p < 0.0001). A significant improvement in time to initiating DMARDs from 2012 [48 (24-96) months] to 2017 [12 (6-36) months] (p < 0.0001) and from 2017 to 2021 [12 (5-24) months] (p = 0.03) was seen. Higher education, more patients opting for treatment from rheumatologists, and urbanisation contributed significantly to improvement in delay. There was no impact of age or gender on delay. CONCLUSION: Delay in diagnosis has improved significantly between 2012 and 2021. However, delay still remains long as most patients miss the 3-month therapeutic window. Future work focussing on reasons for delays in the patient pathway could help improve consultation pathways in India.

Number of days required to measure sedentary time and physical activity using accelerometery in rheumatoid arthritis: a reliability study.

This study aimed to determine the minimum number of days required to reliably estimate free-living sedentary time, light-intensity physical activity (LPA) and moderate-intensity physical activity (MPA) using accelerometer data in people with Rheumatoid Arthritis (RA), according to Disease Activity Score-28-C-reactive protein (DAS-28-CRP). Secondary analysis of two existing RA cohorts with controlled (cohort 1) and active (cohort 2) disease was undertaken. People with RA were classified as being in remission (DAS-28-CRP < 2.4, n = 9), or with low (DAS-28-CRP ≥ 2.4-≤ 3.2, n = 15), moderate (DAS-28-CRP > 3.2-≤ 5.1, n = 41) or high (DAS-28-CRP > 5.1, n = 16) disease activity. Participants wore an ActiGraph accelerometer on their right hip for 7 days during waking hours. Validated RA-specific cut-points were applied to accelerometer data to estimate free-living sedentary time, LPA and MPA (%/day). Single-day intraclass correlation coefficients (ICC) were calculated and used in the Spearman Brown prophecy formula to determine the number of monitoring days required to achieve measurement reliability (ICC ≥ 0.80) for each group. The remission group required ≥ 4 monitoring days to achieve an ICC ≥ 0.80 for sedentary time and LPA, with low, moderate and high disease activity groups requiring ≥ 3 monitoring days to reliably estimate these behaviours. The monitoring days required for MPA were more variable across disease activity groups (remission = ≥ 3 days; low = ≥ 2 days; moderate = ≥ 3 days; high = ≥ 5 days). We conclude at least 4 monitoring days will reliably estimate sedentary time and LPA in RA, across the whole spectrum of disease activity. However, to reliably estimate behaviours across the movement continuum (sedentary time, LPA, MPA), at least 5 monitoring days are required.

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.

Perceptions and experiences of individuals at-risk of rheumatoid arthritis (RA) knowing about their risk of developing RA and being offered preventive treatment: systematic review and thematic synthesis of qualitative studies.

OBJECTIVES: There is increasing interest in identifying individuals at-risk of rheumatoid arthritis (RA) and initiating early treatment to prevent or delay the onset of arthritis. We aimed to describe the perceptions and experiences of at-risk individuals and to inform the conduct of clinical trials and studies, and clinical practice. METHODS: A systematic review and thematic synthesis of qualitative studies was conducted. Two review authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist and assessed confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative Research approach. RESULTS: Seven studies involving 115 individuals at-risk of developing RA were included. Three major themes (seven subthemes) were identified: understanding the risk of developing RA (knowledge of RA and identification of potential risk factors); preventive interventions to reduce the risk of developing RA (understanding the value and role of preventive interventions, and engagement with preventive interventions); and perceptions of predictive testing for RA (benefits of predictive testing, decision to undertake predictive testing and concerns about predictive testing). Moderate confidence in most review findings was evident. CONCLUSION: While there are clear benefits in informing individuals at-risk of RA about their risk following predictive testing and offering preventive treatment, there are potential barriers to engagement, intensified by the burden of uncertainty. Identification of the optimum approaches for presenting risk information, including the risks and benefits of engaging with preventive interventions, is urgently needed to support individuals at-risk of RA in their decision making. PROSPERO REGISTRATION NUMBER: CRD42021236034.

Predictors of interest in predictive testing for rheumatoid arthritis among first degree relatives of rheumatoid arthritis patients.

OBJECTIVES: There is increasing interest in prediction and prevention of RA. It is important to understand the views of those at risk to inform the development of effective approaches. First-degree relatives (FDRs) of RA patients are at increased risk of RA. This study assessed predictors of their interest in predictive testing for RA. METHODS: Questionnaires were completed by RA patients (provided with their questionnaire by a healthcare professional) and their FDRs (provided with their questionnaire by their RA proband). FDR surveys assessed interest in taking a predictive test, demographic variables, perceived RA risk, attitudes about predictive testing, autonomy preferences, illness perceptions, avoidance coping and health anxiety. Patient surveys included demographic variables, disease impact, RA duration and treatment. Ordinal logistic regression examined the association between FDRs' characteristics and their interest in predictive testing. Generalized estimating equations assessed associations between patient characteristics and FDRs' interest in predictive testing. RESULTS: Three hundred and ninety-six FDRs responded. Paired data from the RA proband were available for 292. The proportion of FDRs interested in predictive testing was 91.3%. Information-seeking preferences, beliefs that predictive testing can increase empowerment over health and positive attitudes about risk knowledge were associated with increased interest. Beliefs that predictive testing could cause psychological harm predicted lower interest. Patient characteristics of the proband were not associated with FDRs' interest. CONCLUSIONS: FDRs' interest in predictive testing for RA was high, and factors associated with interest were identified. These findings will inform the development of predictive strategies and informational resources for those at risk.

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.

11ß-Hydroxysteroid Dehydrogenase Type 1 within Osteoclasts Mediates the Bone Protective Properties of Therapeutic Corticosteroids in Chronic Inflammation.

Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11ß-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg11ßKO), mesenchymal (including osteoblast) (TNF-tg11ßflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11ßflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11ß-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11ß-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11ß-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11ß-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11ß-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11ß-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease.

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.

EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis.

BACKGROUND: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA). METHODS: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC. RESULTS: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach. CONCLUSION: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

Type 2 diabetes mellitus, glycaemic control, associated therapies and risk of rheumatoid arthritis: a retrospective cohort study.

OBJECTIVE: To compare the incident risk of RA in patients with type 2 diabetes mellitus (T2DM) and to explore the role of glycaemic control and associated therapeutic use in the onset of RA. METHODS: This study was a retrospective cohort study using patients derived from the IQVIA Medical Research Data (IMRD-UK) database between 1995 and 2019. A total of 224 551 newly diagnosed patients with T2DM were matched to 449 101 patients without T2DM and followed up to assess their risk of RA. Further analyses investigated the effect of glycaemic control, statin use and anti-diabetic drugs on the relationship between T2DM and RA using a time-dependent Cox regression model. RESULTS: During the study period, the incidence of RA was 8.1 and 10.6 per 10 000 person-years in the exposed and unexposed groups, respectively. The adjusted hazard ratio (aHR) was 0.73 (95% CI 0.67, 0.79). In patients who had not used statins in their lifetime, the aHR was 0.89 (95% CI 0.69, 1.14). When quantifying the effects of glycaemic control, anti-diabetic drugs and statins using time-varying analyses, there was no association with glycaemic control [aHR 1.00 (95% CI 0.99, 1.00)], use of metformin [aHR 1.00 (95% CI 0.82, 1.22)], dipeptidyl peptidase-4 inhibitors [DPP4is; aHR 0.94 (95% CI 0.71, 1.24)] and the development of RA. However, statins demonstrated a protective effect for progression of RA in those with T2DM [aHR 0.76 (95% CI 0.66, 0.88)], with evidence of a duration-response relationship. CONCLUSION: There is a reduced risk of RA in patients with T2DM that may be attributable to the use of statins.

Nurse-led care for the management of rheumatoid arthritis: a review of the global literature and proposed strategies for implementation in Africa and the Middle East.

Globally, increasing demand for rheumatology services has led to a greater reliance on non-physician healthcare professionals (HCPs), such as rheumatology nurse specialists, to deliver care as part of a multidisciplinary team. Across Africa and the Middle East (AfME), there remains a shortage of rheumatology HCPs, including rheumatology nurses, which presents a major challenge to the delivery of rheumatology services, and subsequently the treatment and management of conditions such as rheumatoid arthritis (RA). To further explore the importance of nurse-led care (NLC) for patients with RA and create a set of proposed strategies for the implementation of NLC in the AfME region, we used a modified Delphi technique. A review of the global literature was conducted using the PubMed search engine, with the most relevant publications selected. The findings were summarized and presented to the author group, which was composed of representatives from different countries and HCP disciplines. The authors also drew on their knowledge of the wider literature to provide context. Overall, results suggest that NLC is associated with improved patient perceptions of RA care, and equivalent or superior clinical and cost outcomes versus physician-led care in RA disease management. Expert commentary provided by the authors gives insights into the challenges of implementing nurse-led RA care. We further report practical proposed strategies for the development and implementation of NLC for patients with RA, specifically in the AfME region. These proposed strategies aim to act as a foundation for the introduction and development of NLC programs across the AfME region.

Global Deletion of 11ß-HSD1 Prevents Muscle Wasting Associated with Glucocorticoid Therapy in Polyarthritis.

Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11ß-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11ß-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11ß-HSD1 global knock-out (11ßKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11ß-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11ßKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11ßKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11ßKO compared to TNF-tg mice. In summary, 11ß-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11ß-HSD1 may offer a strategy to refine the safety of glucocorticoids.