Influence of Social Support, Financial Status, and Lifestyle on the Disparity Between Inflammation and Disability in Rheumatoid Arthritis.

OBJECTIVE: To investigate how social support, financial status, and lifestyle influence the development of excess disability in rheumatoid arthritis (RA). METHODS: Data were obtained from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort study of people with RA. A previous analysis identified groups with similar inflammation trajectories but markedly different disability over 10 years; those in the higher disability trajectory groups were defined as having "excess disability." Self-reported data regarding contextual factors (social support, financial situation, lifestyle) were obtained from participants, and they completed patient-reported outcome measures (pain, fatigue, anxiety, depression) at baseline. The direct effect of the contextual factors on excess disability and the effect mediated by patient-reported outcome measures were assessed using structural equation models. Findings were validated in 2 independent data sets (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN]). RESULTS: Of 538 included ESPOIR participants (mean age ± SD 48.3 ± 12.2 years; 79.2% women), 200 participants (37.2%) were in the excess disability group. Less social support (ß = 0.17 [95% confidence interval (95% CI) 0.08, 0.26]), worse financial situation (ß = 0.24 [95% CI 0.14, 0.34]), less exercise (ß = 0.17 [95% CI 0.09-0.25]), and less education (ß = 0.15 [95% CI 0.06, 0.23]) were associated with excess disability group membership; smoking, alcohol consumption, and body mass index were not. Fatigue and depression mediated a small proportion of these effects. Similar results were seen in NOAR and ERAN. CONCLUSION: Greater emphasis is needed on the economic and social contexts of individuals with RA at presentation; these factors might influence disability over the following decade.

Cognitive impairment in the immune-mediated inflammatory diseases compared with age-matched controls: Systematic review and meta-regression.

OBJECTIVES: To compare the magnitude of cognitive impairment against age-expected levels across the immune mediated inflammatory diseases (IMIDs: systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], axial spondyloarthritis [axSpA], psoriatic arthritis [PsA], psoriasis [PsO]). METHODS: A pre-defined search strategy was implemented in Medline, Embase and Psychinfo on 29/05/2021. Inclusion criteria were: (i) observational studies of an IMID, (ii) healthy control comparison, (iii) measuring cognitive ability (overall, memory, complex attention/executive function, language/verbal fluency), and (iv) sufficient data for meta-analysis. Standardised mean differences (SMD) in cognitive assessments between IMIDs and controls were pooled using random-effects meta-analysis. IMIDs were compared using meta-regression. RESULTS: In total, 65 IMID groups were included (SLE: 39, RA: 19, axSpA: 1, PsA: 2 PsO: 4), comprising 3141 people with IMIDs and 9333 controls. People with IMIDs had impairments in overall cognition (SMD: -0.57 [95% CI -0.70, -0.43]), complex attention/executive function (SMD -0.57 [95% CI -0.69, -0.44]), memory (SMD -0.55 [95% CI -0.68, -0.43]) and language/verbal fluency (SMD -0.51 [95% CI -0.68, -0.34]). People with RA and people with SLE had similar magnitudes of cognitive impairment in relation to age-expected levels. People with neuropsychiatric SLE had larger impairment in overall cognition compared with RA. CONCLUSIONS: People with IMIDs have moderate impairments across a range of cognitive domains. People with RA and SLE have similar magnitudes of impairment against their respective age-expected levels, calling for greater recognition of cognitive impairment in both conditions. To further understand cognition in the IMIDs, more large-scale, longitudinal studies are needed.

HLA-DRB1 haplotypes predict cardiovascular mortality in inflammatory polyarthritis independent of CRP and anti-CCP status.

BACKGROUND: Haplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA) are associated with radiological outcome, anti-TNF response and all cause-mortality in RA. RA is associated with cardiovascular (CV) morbidity and mortality, but the increased prevalence of risk factors of CV disease in RA only partially explains this association. The aim of this study was to investigate whether amino acids at positions 11, 71 and 74 of HLA-DRB1 are associated with cardiovascular (CV) mortality in inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register (NOAR) is an incidence register of IP: recruitment 1990-2007, final follow-up 2011. Two thousand five hundred fourteen patients had available genetic and mortality data. Amino acids at positions 11, 71 and 74 of HLA-DRB1 were determined. Univariate Cox proportional hazard models were applied to assess the association of genetic markers and both all-cause mortality and cardiovascular mortality. RESULTS: Among 2514 participants, 643 (25.6%) died during the study, and 343 (53.3%) of these deaths were attributed to CV causes. One thousand six hundred fifty (65.6%) participants were female, 709 (32.3%) were anti-CCP-positive and the median age of participants was 54. HLA-DRB1 haplotypes associated with susceptibility to rheumatoid arthritis (RA) consistently show the same magnitude and direction of association for overall and CV mortality in IP. For example, the SEA-haplotype, associated with the lowest susceptibility to RA, and the best radiographic outcome, was found to be associated with decreased CV mortality (HR 0.67, 95% CI 0.47, 0.91, p=0.023). Mediation analysis revealed associations were independent of anti-CCP status. CONCLUSIONS: HLA-DRB1 haplotypes associated with susceptibility to RA also predispose to increased risk of CV mortality in IP, independent of known CV risk factors. Associations were independent of anti-CCP status, which suggests in the future, genetic factors will add to the prediction of risk of cardiovascular mortality beyond serological markers.

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis.

OBJECTIVES: To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation. METHODS: Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, <24 months baseline symptom duration, and disability (HAQ) and inflammation [two-component DAS28 (DAS28-2C)] recorded at baseline and at one other follow-up. People in each cohort also completed patient-reported outcome measures at each assessment (pain, fatigue, depressive symptoms). Group-based trajectory models were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up. RESULTS: This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8); women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories. CONCLUSION: Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.

Reduced cognitive ability in people with rheumatoid arthritis compared with age-matched healthy controls.

OBJECTIVE: The aim was to compare the cognitive ability of people with RA with healthy controls (HCs). METHODS: People with RA were recruited from the Norfolk Arthritis Register (NOAR), a population-based cohort study of people with inflammatory arthritis. Data on aged-matched HCs (people with no cognitive impairment) came from the comparison arm of The Dementia Research and Care Clinic Study (TRACC). People with RA and HCs performed a range of cognitive ability tasks to assess attention, memory, verbal fluency, language, visuospatial skills, emotional recognition, executive function and theory of mind. A score of <88 on the Addenbrooke's Cognitive Examination III was considered cognitive impairment. Scores were compared using linear regression adjusting for age, sex, smoking status, education, BMI, anxiety and depression. RESULTS: Thirty-eight people with RA [mean (S.D.) age: 69.1 (8.0) years; 25 (65.8%) women] were matched with 28 HCs [mean (S.D.) age: 68.2 (6.4) years; 15 (53.6%) women]. Twenty-three (60.5%) people with RA were considered to have mild cognitive impairment [mean (S.D.) Addenbrooke's Cognitive Examination III: RA = 85.2 (7.4), HC = 96.0 (2.5)]. People with RA had impairments in memory, verbal fluency, visuospatial functioning, executive function and emotional recognition in faces compared with HCs, after adjustment for confounders. CONCLUSION: People with RA had cognitive impairments in a range of domains. People with RA might benefit from cognitive impairment screening to allow for early administration of appropriate interventions.

Impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases in the UK: a mixed-methods study.

OBJECTIVES: To determine the impact of COVID-19 pandemic social restriction measures on people with rheumatic and musculoskeletal diseases (RMDs) and to explore how people adapted to these measures over time. DESIGN: Mixed-methods investigation comprising a national online longitudinal survey and embedded qualitative study. SETTING: UK online survey and interviews with community-dwelling individuals in the East of England. PARTICIPANTS: People in the UK with RMDs were invited to participate in an online survey. A subsection of respondents were invited to participate in the embedded qualitative study. PRIMARY AND SECONDARY OUTCOME MEASURES: The online survey, completed fortnightly over 10 weeks from April 2020 to August 2020, investigated changes in symptoms, social isolation and loneliness, resilience and optimism. Qualitative interviews were undertaken assessing participant's perspectives on changes in symptoms, exercising, managing instrumental tasks such a shopping, medication and treatment regimens and how they experienced changes in their social networks. RESULTS: 703 people with RMDs completed the online survey. These people frequently reported a deterioration in symptoms as a result of COVID-19 pandemic social restrictions (52% reported increase vs 6% reported a decrease). This was significantly worse for those aged 18-60 years compared with older participants (p=0.017). The qualitative findings from 26 individuals with RMDs suggest that the greatest change in daily life was experienced by those in employment. Although some retired people reported reduced opportunity for exercise outside their homes, they did not face the many competing demands experienced by employed people and people with children at home. CONCLUSIONS: People with RMDs reported a deterioration in symptoms when COVID-19 pandemic social restriction measures were enforced. This was worse for working-aged people. Consideration of this at-risk group, specifically for the promotion of physical activity, changing home-working practices and awareness of healthcare provision is important, as social restrictions continue in the UK.

The reliability of radiographic measures of total ankle replacement position: an analysis from the OARS cohort.

OBJECTIVE: There is no validated radiographic measurement to diagnose prosthetic complication(s) following total ankle replacements (TARs) although a number of angular and linear measurements, used to define the TAR position on postoperative radiographs, have been recommended to detect prosthetic loosening. The aim of this study was to test the intra- and interobserver reliability of these measurements. MATERIALS AND METHODS: This is a prospective study embedded within a multicentre cohort study. Following sample size calculation, 62 patients were analysed. Six measurements were performed on the first postoperative anteroposterior and lateral ankle radiographs: angles α and ß, and length "a" defined the craniocaudal position of the tibial component, while angle γ, and lengths "b" and "c" defined the angular position of the talar component. Measurements were recorded by three independent observers. Inter- and intraobserver reliability was assessed with intraclass correlation coefficient (ICC), Bland-Altman plots, and within-subject coefficients of variation (CV). RESULTS: The intrarater ICC was "almost perfect" (ICC 0.83-0.97) for all six measurements. The interrater ICC was "substantial" to "almost perfect" (ICC 0.69-0.93). The mean difference in intrarater angular measurements was ≤ 0.6° and ≤ 0.8 mm for linear measurements, and ≤ 2.2° and ≤ 2.1 mm for interrater measurements. Maximum CV for the interrater linear measurements (≤ 17.7%) more than doubled that of the angular measurements (≤ 8.0%). The maximum width of the 95% limits of agreement was 6.5° and 8.4 mm for intrarater measures, and 8.9° and 10.6 mm for interrater measurements. CONCLUSION: Angular measures are more reliable than linear measures and have potential in routine clinical practice for TAR position assessment.

Analysis of change in patient-reported outcome measures with floor and ceiling effects using the multilevel Tobit model: a simulation study and an example from a National Joint Register using body mass index and the Oxford Hip Score.

OBJECTIVES: This study has three objectives. (1) Investigate the association between body mass index (BMI) and the efficacy of primary hip replacement using a patient-reported outcome measure (PROMs) with a measurement floor and ceiling, (2) Explore the performance of different estimation methods to estimate change in PROMs score following surgery using a simulation study and real word data where data has measurement floors and ceilings and (3) Lastly, develop guidance for practising researchers on the analysis of PROMs in the presence of floor and ceiling effects. DESIGN: Simulation study and prospective national medical device register. SETTING: National Register of Joint Replacement and Medical Devices. METHODS: Using a Monte Carlo simulation study and data from a national joint replacement register (162 513 patients with pre- and post-surgery PROMs), we investigate simple approaches for the analysis of outcomes with floor and ceiling effects that are measured at two occasions: linear and Tobit regression (baseline adjusted analysis of covariance, change-score analysis, post-score analysis) in addition to linear and multilevel Tobit models. PRIMARY OUTCOME: The primary outcome of interest is change in PROMs from pre-surgery to 6 months post-surgery. RESULTS: Analysis of data with floor and ceiling effects with models that fail to account for these features induce substantial bias. Single-level Tobit models only correct for floor or ceiling effects when the exposure of interest is not associated with the baseline score. In observational data scenarios, only multilevel Tobit models are capable of providing unbiased inferences. CONCLUSIONS: Inferences from pre- post-studies that fail to account for floor and ceiling effects may induce spurious associations with substantial risk of bias. Multilevel Tobit models indicate the efficacy of total hip replacement is independent of BMI. Restricting access to total hip replacement based on a patients BMI can not be supported by the data.

Demographic and geographical variability in physiotherapy provision following hip and knee replacement. An analysis from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

BACKGROUND: Total hip (THR) and knee replacement (TKR) are two of the most common elective orthopaedic procedures worldwide. Physiotherapy is core to the recovery of people following joint replacement. However, there remains uncertainty as to physiotherapy provision at a national level. OBJECTIVES: To examine the relationship between patient impairment and geographical variation on the provision of physiotherapy among patients who undergo primary total hip or knee replacement (THR/TKR). DESIGN: Population-based observational cohort study. METHODS: Patients undergoing THR (n=17,338) or TKR (n=20,260) recorded in the National Joint Registry for England (NJR) between 2009 and 2010 and completed Patient Reported Outcome Measures (PROMs) questionnaires at Baseline and 12 months postoperatively. Data were analysed on the frequency of physiotherapy over the first postoperative year across England's Strategic Health Authorities (SHAs). Logistic regression analyses examined the relationship between a range of patient and geographical characteristics and physiotherapy provision. RESULTS: Following THR, patients were less likely to receive physiotherapy than following TKR patients ('some' treatment by a physiotherapist within 1st post operative year: 53% vs 79%). People with worse functional outcomes 12 months postoperatively, received more physiotherapy after THR and TKR. There was substantial variation in provision of physiotherapy according to age (younger people received more physiotherapy), gender (females received more physiotherapy) ethnicity (non-whites received more physiotherapy) and geographical location (40% of patients from South West received some physiotherapy compared to 40 73% in London after THR). CONCLUSIONS: There is substantial variation in the provision of physiotherapy nationally. This variation is not explained by differences in the patient's clinical presentation.

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.

The effectiveness of a multidisciplinary intervention strategy for the treatment of symptomatic joint hypermobility in childhood: a randomised, single Centre parallel group trial (The Bendy Study).

INTRODUCTION: Joint hypermobility is common in childhood and can be associated with musculoskeletal pain and dysfunction. Current management is delivered by a multidisciplinary team, but evidence of effectiveness is limited. This clinical trial aimed to determine whether a structured multidisciplinary, multisite intervention resulted in improved clinical outcomes compared with standard care. METHOD: A prospective randomised, single centre parallel group trial comparing an 8-week individualised multidisciplinary intervention programme (bespoke physiotherapy and occupational therapy in the clinical, home and school environment) with current standard management (advice, information and therapy referral if deemed necessary). The primary endpoint of the study was between group difference in child reported pain from baseline to 12 months as assessed using the Wong Baker faces pain scale. Secondary endpoints were parent reported pain (100 mm visual analogue scale), parent reported function (child health assessment questionnaire), child reported quality of life (child health utility 9-dimensional assessment), coordination (movement assessment battery for children version 2) and grip strength (handheld dynamometer). RESULTS: 119 children aged 5 to 16 years, with symptomatic hypermobility were randomised to receive an individualised multidisciplinary intervention (I) (n = 59) or standard management (S) (n = 60). Of these, 105 completed follow up at 12 months. No additional significant benefit could be shown from the intervention compared to standard management. However, there was a statistically significant improvement in child and parent reported pain, coordination and grip strength in both groups. The response was independent of the degree of hypermobility. CONCLUSION: This is the first randomised controlled trial to compare a structured multidisciplinary, multisite intervention with standard care in symptomatic childhood hypermobility. For the majority, the provision of education and positive interventions aimed at promoting healthy exercise and self-management was associated with significant benefit without the need for more complex interventions. TRIAL REGISTRATION: The trial was registered prospectively with the national database at the Clinical Research Network (UKCRN Portfolio 9366). The trial was registered retrospectively with ISRCTN ( ISRCTN86573140 ).

Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study.

BACKGROUND: Oral methotrexate (MTX) is the first-line therapy for patients with rheumatoid arthritis (RA). However, approximately one quarter of patients discontinue MTX within 12 months. MTX failure, defined as MTX cessation or the addition of another anti-rheumatic drug, is usually due adverse event(s) and/or inefficacy. The aims of this study were to evaluate the rate and predictors of oral MTX failure. METHODS: Subjects were recruited from the Norfolk Arthritis Register (NOAR), a primary care-based inception cohort of patients with early inflammatory polyarthritis (IP). Subjects were eligible if they commenced MTX as their first DMARD and were recruited between 2000 and 2008. Patient-reported reasons for MTX failure were recorded and categorised as adverse event, inefficacy or other. The addition of a second DMARD during the study period was categorised as failure due to inefficacy. Cox proportional hazards regression models were used to assess potential predictors of MTX failure, accounting for competing risks. RESULTS: A total of 431 patients were eligible. The probability of patients remaining on MTX at 2 years was 82%. Competing risk analysis revealed that earlier MTX failure due to inefficacy was associated with rheumatoid factor (RF) positivity, younger age at symptom onset and higher baseline disease activity (DAS-28). MTX cessation due to an adverse event was less likely in the RF-positive cohort. CONCLUSIONS: RF-positive inflammatory polyarthritis patients who are younger with higher baseline disease activity have an increased risk of MTX failure due to inefficacy. Such patients may require combination therapy as a first-line treatment.

Trajectory of physical activity after hip fracture: An analysis of community-dwelling individuals from the English Longitudinal Study of Ageing.

INTRODUCTION: To analyse physical activity participation in a community-dwelling people in England with hip fracture the interval prior to fracture, in the fracture recovery period, and a minimum of two years post-fracture. MATERIALS AND METHODS: 215 individuals were identified from the English Longitudinal Study of Ageing cohort (2002-2014) who sustained a hip fracture following a fall and for whom data were available on physical activity participation relating to the period pre-fracture, within-fracture recovery phase and post-fracture (minimum of two years). Physical activity was assessed using the validated ELSA physical activity questionnaire. Prevalence of 'low' physical activity participation was calculated and multi-level modelling analyses were performed to explore physical activity trajectories over the follow-up phase, and whether age, depression, gender and frailty were associated with physical activity participation. RESULTS: Prevalence of low physical activity participation within two years prior to hip fracture was 16.7% (95% Confidence Intervals (CI): 11.6% to 21.8%). This increased at the final follow-up phase to 21.3% (95% CI: 15.1% to 27.6%). This was not a statistically significant change (P = 0.100). Age (P = 0.005) and frailty (P < 0.001) were statistically significant explanatory variables (P = 0.005) where older age and greater frailty equated to lower physical activity participation. Neither gender (P = 0.288) nor depression (P = 0.121) were significant explanatory variables. CONCLUSION: Physical activity levels do not significantly change between pre-fracture to a minimum of two years post-hip fracture for community-dwelling individuals. This contrasts with previous reports of reduced mobility post-hip fracture, suggesting that 'physical activity' and 'mobility' should be considered as separate outcomes in this population.

Trajectory of social isolation following hip fracture: an analysis of the English Longitudinal Study of Ageing (ELSA) cohort.

Background: social isolation is defined as a lack of meaningful and sustained communication or interactions with social networks. There is limited understanding on the prevalence of social isolation and loneliness in people following hip fracture and no previous understanding of how this changes over time. Objective: to determine the prevalence and trajectory of social isolation and loneliness before a hip fracture, during the recovery phase and a minimum of 2 years post-hip fracture in an English population. Methods: data were from the English Longitudinal Study of Ageing (ELSA) cohort (2004/5-2014/15). The sample comprised of 215 participants who had sustained a hip fracture. Measures of social isolation and loneliness were analysed through multilevel modelling to determine their trajectories during three-time intervals (pre-fracture; interval at hip fracture and recovery; minimum 2 years post-fracture). The prevalence of social isolation and loneliness were determined pre- and post-fracture. Results: prevalence of social isolation was 19% post-hip fracture and loneliness 13% post-hip fracture. There was no statistically significant change in social isolation pre-fracture compared to a minimum of 2 years post-fracture (P = 0.78). Similarly, there was no statistically significant change in loneliness pre-fracture compared to a minimum of 2 years post-fracture (P = 0.12). Conclusion: this analysis has determined that whilst social isolation and loneliness do not change over time following hip fracture, these remain a significant problem for this population. Interventions are required to address these physical and psychological health needs. This is important as they may have short and longer term health benefits for people post-hip fracture.

Primary care challenges in diagnosing and referring patients with suspected rheumatoid arthritis: a national cross-sectional GP survey.

OBJECTIVE: National guidelines advocate referring patients with persistent synovitis to rheumatology within 3 working days of presentation to primary care. This occurs infrequently. We aimed to identify modifiable barriers to early referral of suspected RA patients among English general practitioners (GPs). METHODS: We carried out a national cross-sectional survey of 1388 English GPs (RA Questionnaire for GPs [RA-QUEST] study). Questions addressed GPs' confidence in diagnosing RA, clinical factors influencing RA diagnosis/referral, timeliness of referrals and secondary care access. Data were captured using 10-point visual analog scales, five-point Likert scales, yes/no questions or free text, and were analysed descriptively. RESULTS: Small joint swelling and pain were most influential in diagnosing RA (91 and 84% rated the importance of these as 4 or 5 on a five-point Likert scale, respectively); investigations including RF (61% rating 4 or 5) and anti-CCP antibody (72% rating 4 or 5) were less influential. Patient history had the greatest impact on the decision to refer (92% rating this 4 or 5 on a 5-point Likert scale), with acute phase markers (74% rating 4 or 5) and serology (76% rating 4 or 5) less impactful. Despite the importance placed on history and examination, only 26% referred suspected RA immediately without investigations; 95% of GPs organizing further tests opted to test for RF. CONCLUSION: For suspected RA patients to be referred within 3 days of presentation to primary care there needs to be a paradigm shift in GPs' approaches to making referral decisions, with a focus on clinical history and examination findings, and not the use of investigations such as RF.

Drug-microbiota interactions and treatment response: Relevance to rheumatoid arthritis.

Knowledge about associations between changes in the structure and/or function of intestinal microbes (the microbiota) and the pathogenesis of various diseases is expanding. However, interactions between the intestinal microbiota and different pharmaceuticals and the impact of these on responses to treatment are less well studied. Several mechanisms are known by which drug-microbiota interactions can influence drug bioavailability, efficacy, and/or toxicity. This includes direct activation or inactivation of drugs by microbial enzymes which can enhance or reduce drug effectiveness. The extensive metabolic capabilities of the intestinal microbiota make it a hotspot for drug modification. However, drugs can also influence the microbiota profoundly and change the outcome of interactions with the host. Additionally, individual microbiota signatures are unique, leading to substantial variation in host responses to particular drugs. In this review, we describe several known and emerging examples of how drug-microbiota interactions influence the responses of patients to treatment for various diseases, including inflammatory bowel disease, type 2 diabetes and cancer. Focussing on rheumatoid arthritis (RA), a chronic inflammatory disease of the joints which has been linked with microbial dysbiosis, we propose mechanisms by which the intestinal microbiota may affect responses to treatment with methotrexate which are highly variable. Furthering our knowledge of this subject will eventually lead to the adoption of new treatment strategies incorporating microbiota signatures to predict or improve treatment outcomes.

Changes in physical activity following total hip or knee arthroplasty: a matched case-control study from the EPIC-Norfolk cohort.

OBJECTIVE: To assess self-reported physical activity changes pre- compared to post-operatively in patients undergoing total hip or knee arthroplasty, and to compare this to an age- and gender-matched cohort of people who have not undergone arthroplasty. DESIGN: Population-based prospective cohort study. SETTING: Norfolk, United Kingdom. SUBJECTS: People who had undergone hip or knee arthroplasty, compared to an age- and gender-matched non-arthroplasty cohort. INTERVENTION: Primary total hip or knee arthroplasty. MAIN MEASURES: Physical activity, measured using the EPIC Physical Activity Questionnaire (EPAQ2). RESULTS: A total of 400 people from the EPIC-Norfolk community cohort were identified who had undergone hip or knee arthroplasty. In all, 767 people were identified to form an age- and gender-matched non-arthroplasty cohort. Mean post-operative follow-up was 43 months post-total hip and 41 months post-total knee arthroplasty. There was a statistically significant reduction from pre- to post-arthroplasty in the number of flights of stairs climbed weekly (hip: mean difference (MD): 6.8; P < 0.01; knee: MD: 10.2; P < 0.01), duration of walking (hip: MD: 1.4 hours/week; P = .02; knee: MD: 2.2 hours/week; P < 0.01) and duration of total recreational activity (hip: MD: 1.1 hours/week; P = 0.02). Compared to the non-arthroplasty cohort, duration of physical activity was lower post-total hip arthroplasty (MD: 1.8 hours/week; P = 0.01). The number of flights of stairs climbed weekly (MD: 12.0; P < 0.01), total recreational activity (MD: 1.7 hours/week; P = 0.04) and physical activity energy expenditure (MD: 5.7 Mets-hours/week; P = 0.05) were lower for people post-total knee arthroplasty compared to the matched controls. CONCLUSIONS: Physical activity did not increase, and in some instances decreased, following total hip or knee arthroplasty.

Can Rheumatologists Predict Eventual Need for Orthopaedic Intervention in Patients with Rheumatoid Arthritis? Results of a Systematic Review and Analysis of Two UK Inception Cohorts.

PURPOSE OF REVIEW: The structural damage caused by rheumatoid arthritis (RA) can often be mitigated by orthopaedic surgery in late disease. This study evaluates the value of predictive factors for orthopaedic intervention. METHODS: A systematic review of literature was undertaken to identify papers describing predictive factors for orthopaedic surgery in RA. Manuscripts were selected if they met inclusion criteria of cohort study design, diagnosis of RA, follow-up duration/disease duration ≥3 years, any orthopaedic surgical interventions recorded, and then summarised for predictive factors. A separate predictive analysis was performed on two consecutive UK Early RA cohorts, linked to national datasets. RECENT FINDINGS: The literature search identified 15 reports examining predictive factors for orthopaedic intervention, 4 inception, 5 prospective and 6 retrospective. Despite considerable variation, acute phase, x-ray scores, women and genotyping were the most commonly reported prognostic markers. The current predictive analysis included 1602 procedures performed in 711 patients (25-year cumulative incidence 26%). Earlier recruitment year, erosions and lower haemoglobin predicted both intermediate and major surgery (P<0.05). Studies report variations in type of and predictive power of clinical and laboratory parameters for different surgical interventions suggesting specific contributions from different pathological and/or patient-level factors. Our current analysis suggests that attention to non-inflammatory factors in addition to suppression of inflammation is needed to minimise the burden of orthopaedic surgery.

Genome-wide methylation analysis of a large population sample shows neurological pathways involvement in chronic widespread musculoskeletal pain.

Chronic widespread musculoskeletal pain (CWP), has a considerable heritable component, which remains to be explained. Epigenetic factors may contribute to and account for some of the heritability estimate. We analysed epigenome-wide methylation using MeDIPseq in whole blood DNA from 1708 monozygotic and dizygotic Caucasian twins having CWP prevalence of 19.9%. Longitudinally stable methylation bins (lsBINs), were established by testing repeated measurements conducted ≥3 years apart, n = 292. DNA methylation variation at lsBINs was tested for association with CWP in a discovery set of 50 monozygotic twin pairs discordant for CWP, and in an independent dataset (n = 1608 twins), and the results from the 2 samples were combined using Fisher method. Functional interpretation of the most associated signals was based on functional genomic annotations, gene ontology, and pathway analyses. Of 723,029 signals identified as lsBINs, 26,399 lsBINs demonstrated the same direction of association in both discovery and replication datasets at nominal significance (P ≤ 0.05). In the combined analysis across 1708 individuals, whereas no lsBINs showed genome-wide significance (P < 10-8), 24 signals reached p≤9E-5, and these included association signals mapping in or near to IL17A, ADIPOR2, and TNFRSF13B. Bioinformatics analyses of the associated methylation bins showed enrichment for neurological pathways in CWP. We estimate that the variance explained by epigenetic factors in CWP is 6%. This, the largest study to date of DNA methylation in CWP, points towards epigenetic modification of neurological pathways in CWP and provides proof of principle of this method in teasing apart the complex risk factors for CWP.

Higher dietary flavonoid intakes are associated with lower objectively measured body composition in women: evidence from discordant monozygotic twins.

Background: Although dietary flavonoid intake has been associated with less weight gain, there are limited data on its impact on fat mass, and to our knowledge, the contribution of genetic factors to this relation has not previously been assessed.Objective: We examined the associations between flavonoid intakes and fat mass.Design: In a study of 2734 healthy, female twins aged 18-83 y from the TwinsUK registry, intakes of total flavonoids and 7 subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, polymers, and proanthocyanidins) were calculated with the use of food-frequency questionnaires. Measures of dual-energy X-ray absorptiometry-derived fat mass included the limb-to-trunk fat mass ratio (FMR), fat mass index, and central fat mass index.Results: In cross-sectional multivariable analyses, higher intake of anthocyanins, flavonols, and proanthocyanidins were associated with a lower FMR with mean ± SE differences between extreme quintiles of -0.03 ± 0.02 (P-trend = 0.02), -0.03 ± 0.02 (P-trend = 0.03), and -0.05 ± 0.02 (P-trend < 0.01), respectively. These associations were not markedly changed after further adjustment for fiber and total fruit and vegetable intakes. In monozygotic, intake-discordant twin pairs, twins with higher intakes of flavan-3-ols (n = 154, P = 0.03), flavonols (n = 173, P = 0.03), and proanthocyanidins (n = 172, P < 0.01) had a significantly lower FMR than that of their co-twins with within-pair differences of 3-4%. Furthermore, in confirmatory food-based analyses, twins with higher intakes of flavonol-rich foods (onions, tea, and pears; P = 0.01) and proanthocyanidin-rich foods (apples and cocoa drinks; P = 0.04) and, in younger participants (aged <50 y) only, of anthocyanin-rich foods (berries, pears, grapes, and wine; P = 0.01) had a 3-9% lower FMR than that of their co-twins.Conclusions: These data suggest that higher habitual intake of a number of flavonoids, including anthocyanins, flavan-3-ols, flavonols, and proanthocyanidins, are associated with lower fat mass independent of shared genetic and common environmental factors. Intervention trials are needed to further examine the effect of flavonoid-rich foods on body composition.