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Background: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis., Objective: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers., Design: Prospective observational cohort study., Setting: Single-center, Leeds, United Kingdom., Participants: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred., Measurements: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done., Results: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years., Limitations: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability., Conclusion: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials., Primary Funding Source: National Institute for Health and Care Research Leeds Biomedical Research Centre., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0272.

Objectives: To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy., Methods: Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV)., Results: Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10 -3 mm Hg -1 (2.7-3.3) vs 4.4×10 -3 mm Hg -1 (3.7-5.2), p<0.001); LV mass significantly lower (78.2 g (74.0-82.7), n=81 vs 92.9 g (84.8-101.7), n=30, p<0.01); and ECV increased (27.1% (26.4-27.9), n=78 vs 24.9% (23.8-26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10 -3 mm Hg -1 (2.7-3.4) to 3.6×10 -3 mm Hg -1 (3.1-4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders., Conclusion: We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers., Trial Registration Number: ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151., Competing Interests: Competing interests: PE has received consultant fees from AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Samsung, Sandoz and UCB and received research grants paid to his employer from AbbVie, BMS, Pfizer, MSD and Roche. MHB has provided expert advice and received consultant fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Pfizer, Roche, Sandoz, Sanofi and UCB and has received research grants paid to her employer from Pfizer Bristol-Myers Squibb, Roche, UCB., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Interosseous tendon inflammation (ITI) has been described in rheumatoid arthritis (RA). Whether ITI occurs in at-risk individuals before the onset of clinical synovitis is unknown., Objectives: To investigate, by MRI, ITI in anti-cyclic citrullinated peptide (CCP)-positive at-risk individuals (CCP +at risk) and to describe the anatomy, prevalence and clinical associations across the RA continuum., Methods: Hand MRI was performed in 93 CCP + at risk, 47 early RA (ERA), 28 established 'late' RA (LRA) and 20 healthy controls (HC) and scored for ITI, flexor tenosynovitis (TSV) and RA MRI scoring at the metacarpophalangeal joints (MCPJs). Cadaveric and histological studies were performed to explore the anatomical basis for MRI ITI., Results: The proportion of subjects with ITI and the number of inflamed interosseous tendons (ITs) increased along the disease continuum (p<0.001): 19% of CCP +at risk, 49% of ERA and 57% of LRA had ≥1 IT inflamed . ITI was not found in any HC. ITI was more frequently identified in tender MCPJs compared with nontender MCPJs (28% vs 12%, respectively). No IT tenosynovial sheath was identified in cadavers on dissection or histological studies suggesting MRI findings represent peritendonitis. Dye studies indicated no communication between the IT and the joint., Conclusions: ITI occurs in CCP + at-risk individuals and can precede the onset of clinical synovitis. The ITs may be important nonsynovial extracapsular targets in the development and progression of RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ultrasound is increasingly used to evaluate shoulder pain, but the benefits of this are unclear. In this study, we examined whether ultrasound-defined pathologies have implications for clinical outcomes., Methods: We extracted reported pathologies from 3000 ultrasound scans of people with shoulder pain referred from primary care. In latent class analysis (LCA), we identified whether individual pathologies clustered in groups. Optimal group number was determined by the minimum Bayesian information criterion. A questionnaire was sent to all patients scanned over a 12-month period (n = 2322). Data collected included demographics, treatments received, current pain and function. The relationship between pathology-defined groups and clinical outcomes was examined., Results: LCA revealed four groups: (1) bursitis with limited inflammation elsewhere (n = 1280), (2) bursitis with extensive inflammation (n = 595), (3) rotator cuff tears (n = 558) and (4) limited pathology (n = 567). A total of 777 subjects (33%) completed questionnaires. The median (IQR) duration post-ultrasound scan was 25 (22-29) months. Subsequent injections were most common in groups 1 and 2 (groups 1-4 76%, 67%, 48% and 61%, respectively); surgery was most common in group 3 (groups 1-4 23%, 21%, 28% and 16%, respectively). Shoulder Pain and Disability Index scores were highest in group 3 (median 48 and 30, respectively) and lowest in group 4 (median 32 and 9, respectively). Patients in group 4 who had surgery reported poor outcomes., Conclusions: In a community-based population, we identified clusters of pathologies on the basis of ultrasound. Our retrospective data suggest that these groups have different treatment pathways and outcomes. This requires replication in a prospective study to determine the value of a pathology-based classification in people with shoulder pain.

Objectives: To determine if quantitative and qualitative shear wave elastography have roles in evaluating musculoskeletal masses., Methods: 105 consecutive patients, prospectively referred for biopsy within a specialist sarcoma centre, underwent B-mode, quantitative (m/s) and qualitative (colour map) shear wave elastography. Reference was histology from subsequent biopsy or excision where possible. Statistical modelling was performed to test elastography data and/or B-mode imaging in predicting malignancy., Results: Of 105 masses, 39 were malignant and 6 had no histology but benign characteristics at 12 months. Radiologist agreement for B-mode and elastography was moderate to excellent Kw 0.52-0.64; PABAKw 0.85-0.90). B-Mode imaging had 78.8% specificity, 76.9% sensitivity for malignancy. Quantitatively, adjusting for age, B-mode and lesion volume there was no statistically significant association between longitudinal velocity and malignancy (OR [95% CI] 0.40[0.10, 1.60], p=0.193), but some evidence that higher transverse velocity was associated with decreased odds of malignancy (0.28[0.06, 1.28], p=0.101). Qualitatively malignant masses tended to be towards the blue spectrum (lower velocities); 39.5% (17/43) of predominantly blue masses were malignant, compared to 14.3% (1/7) of red lesions., Conclusions: Quantitatively and qualitatively there is no statistically significant association between shear wave velocity and malignancy. There is no clear additional role to B-mode imaging currently., Key Points: • Correlation between shear wave velocity and soft tissue malignancy was statistically insignificant • B-mode ultrasound is 76.9 % sensitive and 78.8 % specific • Statistical models show elastography does not significantly add to lesion assessment.

Objectives: No proven treatment exists for ACPA-negative undifferentiated arthritis (UA). The aim of this study was to evaluate whether abatacept is effective in treating poor prognosis, ACPA-negative UA, including its effect on power Doppler on US (PDUS)., Methods: A proof-of-concept, open-label, prospective study of 20 patients with DMARD-naïve, ACPA-negative UA (⩾2 joint synovitis) and PDUS ⩾ 1 with clinical and 20-joint US (grey scale/PDUS) assessments at baseline, 6, 12, 18 and 24 months. All patients received 12 months of abatacept (monotherapy for minimum first 6 months). The primary end point was a composite of the proportion of patients that at 6 months achieved DAS44 remission, a maximum of one swollen joint for at least 3 consecutive months and no radiographic progression (over 0-12 months)., Results: Twenty of the 23 patients screened were enrolled [14 female; mean (sd) age 53.4 (11.2) years, symptom duration 7.5 (0.9) months]. Two (10%) achieved the composite primary end point. A reduction in the mean (sd) DAS44 was observed from a baseline value of 2.66 (0.77) to 2.01 (0.81) at 6 months and to 1.78 (0.95) at 12 months. The DAS44 remission rates were 6/20 (30%; 95% CI: 15, 51%) at 6 months and 8/20 (40%; 95% CI: 22, 62%) at 12 months. A striking decrease in the median (interquartile range; IQR) total PDUS score was noted from 10 (4-23) at baseline to 3 (2-12) and 3 (0-5) at 6 and 12 months, respectively., Conclusion: This report is a first in potentially identifying an effective therapy, abatacept monotherapy, for poor-prognosis, ACPA-negative UA, supported by a clear reduction in PDUS. These data justify evaluation in a controlled study., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To determine whether ultrasound can identify anti-cyclic citrullinated peptide (anti-CCP) antibody-positive patients without clinical synovitis (CS) who progress to inflammatory arthritis (IA)., Methods: In a prospective study, anti-CCP-positive patients without CS underwent ultrasound imaging of 32 joints (wrists, metacarpophalangeal joints, proximal interphalangeal joints and metatarsophalangeal joints (MTPs)) and were monitored for the development of IA. Associations between baseline ultrasound findings (grey scale (GS), power Doppler (PD) and erosions) and (1) progression to IA and (2) development of CS within an individual joint were measured., Results: Consecutive anti-CCP-positive patients (n=136; mean age 51 years, 100 women) were followed up for median of 18.3 months (range 0.1-79.6). At baseline 96% had GS, 30% had PD and 21% had one or more erosions. IA developed in 57 patients (42%) after median of 8.6 months (range 0.1-52.4). Ultrasound abnormalities (GS ≥2, PD ≥1 or erosion ≥1) were found in 86% at baseline compared with 67% of non-progressors (χ 2 =6.3, p=0.012). Progression to IA was significantly higher in those with ultrasound findings in any joint (excluding MTPs for GS) (GS ≥2: 55% vs 24%, HR (95% CI) 2.3 (1.0 to 4.9), p=0.038; PD ≥2: 75% vs 32%, 3.7 (2.0 to 6.9), p<0.001 and erosion ≥1: 71% vs 34%, 2.9 (1.7 to 5.1), p<0.001). Furthermore, progression occurred earlier with PD ≥2 (median 7.1 vs 52.4 months) and erosion ≥1 (15.4 vs 46.5). At the individual joint level, the trend for progression to CS was more significant for GS and PD (GS ≥2: 26% vs 3%, 9.4 (5.1 to 17.5), p<0.001; PD ≥2: 55% vs 4%, 31.3 (15.6 to 62.9), p<0.001)., Conclusion: Ultrasound features of joint inflammation may be detected in anti-CCP-positive patients without CS. Ultrasound findings predict progression (and rate of progression) to IA, with the risk of progression highest in those with PD signal., Trial Registration Number: NCT02012764; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies., Methods: Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values., Results: Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007)., Conclusion: When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX., Trial Registration: EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess whether the "spread" of joint pain is related to pain-associated muscle loss in 1 joint leading to increased loading and subsequent pain in other joints., Methods: Associations between persistent knee pain (pain in 1 or 2 knees over 0-3 years vs no persistent pain) and incident shoulder pain at Year 4 were examined in participants from the longitudinal National Institutes of Health Osteoarthritis Initiative. Associations were assessed using log multinomial modeling, adjusted for age, sex, body mass index, depression score, other lower limb pain, and baseline leg weakness (difficulty standing from a sitting position)., Results: In older adults with clinically significant knee osteoarthritis (OA) or at risk of knee OA (n = 3486), the number of painful joints increased yearly, from 2.1 joints (95% CI 2.0-2.2) at baseline increasing by 5.2% (95% CI 2.2-8.3) at Year 4. Shoulders were the next most commonly affected joints after knees (28.5%). Persistent pain in 1 or 2 knees increased risk of bilateral shoulder pain at Year 4 [1 knee: relative risk (RR) 1.59, 95% CI 0.97-2.61; 2 knees: RR 2.02, 95% CI 1.17-3.49] after adjustment for confounders. Further adjustment for leg weakness attenuated effect sizes (1 knee: RR 1.13, 95% CI 0.60-2.11; 2 knees: RR 1.44, 95% CI 0.75-2.77), indicating mediation by functional leg weakness., Conclusion: Spread of joint pain is not random. Persistently painful knees predict new bilateral shoulder pain, which is likely mediated by leg weakness, suggesting that biomechanical factors influence the spread of pain.

Objectives: Anticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression., Methods: 103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed., Results: Compared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively)., Conclusions: T cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: To evaluate quantitative sonoelastography of benign and malignant musculoskeletal soft tissue masses., Methods: We conducted a prospective study of 50 patients from a specialist sarcoma center who had extremity soft tissue masses referred for biopsy. After consent, the quantitative shear wave velocity (meters per second) was measured in longitudinal and transverse planes (3 readings in each plane and mean calculated). All masses subsequently underwent biopsy, excision, or both, with the histologic diagnosis taken as the reference standard. At a subsequent sitting, all anonymized B-mode sonograms were scored independently by 2 radiologists as benign or malignant with agreement by consensus if necessary., Results: Of the 50 masses, 15 were malignant and 35 benign. Nine masses had incomplete velocity readings. Intraclass correlation coefficients for intra-reader reliability of velocity measurements were highly repeatable. There was preliminary evidence that the longitudinal shear wave velocity of malignant masses was on average 30% slower than that of benign masses (P< .10). Longitudinal and transverse shear wave measurements were moderately associated with each other (P = .003). There was no evidence that shear wave velocity varied with patient age, sex, or mass volume. For B-mode assessment of malignancy, sensitivity (Wilson 90% confidence interval) was 73.3% (52.1%, 87.4%), and specificity was 77.1% (63.8%, 86.6%). Interobserver agreement was substantial (κ= 0.86). Four of 15 malignant masses (26.6%) were incorrectly classified as benign on B-mode assessment (all grade 1 liposarcomas)., Conclusions: These data suggest that shear wave velocity measurement is reproducible and that malignant masses may have slower longitudinal shear wave velocities than benign masses. The sample size of this pilot study precludes adjusted analysis but should form the basis for larger study designs.

Objective: There is growing understanding of the importance of bone in OA. Our aim was to determine the relationship between 3D MRI bone shape and total knee replacement (TKR)., Methods: A nested case-control study within the Osteoarthritis Initiative cohort identified case knees with confirmed TKR for OA and controls that were matched using propensity scores. Active appearance modelling quantification of the bone shape of all knee bones identified vectors between knees having or not having OA. Vectors were scaled such that -1 and +1 represented the mean non-OA and mean OA shapes., Results: Compared to controls (n = 310), TKR cases (n = 310) had a more positive mean baseline 3D bone shape vector, indicating more advanced structural OA, for the femur [mean 0.98 vs -0.11; difference (95% CI) 1.10 (0.88, 1.31)], tibia [mean 0.86 vs -0.07; difference (95% CI) 0.94 (0.72, 1.16)] and patella [mean 0.95 vs 0.03; difference (95% CI) 0.92 (0.65, 1.20)]. Odds ratios (95% CI) for TKR per normalized unit of 3D bone shape vector for the femur, tibia and patella were: 1.85 (1.59, 2.16), 1.64 (1.42, 1.89) and 1.36 (1.22, 1.50), respectively, all P < 0.001. After including Kellgren-Lawrence grade in a multivariable analysis, only the femur 3D shape vector remained significantly associated with TKR [odds ratio 1.24 (1.02, 1.51)]., Conclusion: 3D bone shape was associated with the endpoint of this study, TKR, with femoral shape being most associated. This study contributes to the validation of quantitative MRI bone biomarkers for OA structure-modification trials., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Around 1% of the population test positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies. This biomarker predicts the progression to rheumatoid arthritis (RA) but over a variable time frame. To increase its clinical relevance, this study sought to determine (1) if the proportion of anti-CCP-positive individuals could be enriched by case selection of people attending primary care with new non-specific musculoskeletal (MSK) symptoms but without clinical synovitis (CS) and (2) whether these individuals progress rapidly to inflammatory arthritis (IA), in particular RA., Methods: In this prospective cohort study, individuals aged ≥18 years with new non-specific MSK symptoms, without CS, were recruited from primary care in the UK. Anti-CCP-positive individuals were invited for follow-up in the rheumatology department, Leeds. Those who tested negative were sent questionnaires 12 months later., Results: 2028 individuals were recruited. Of these, 2.8% (57/2028) were anti-CCP positive, of whom 47% (27/57) developed IA - 24 RA, 1 undifferentiated IA (UIA), 2 polymyositis; 92.6% (25/27) within 12 months, median 1.8 months (IQR 1.0-4.3, range 0.3-16.1). Of the anti-CCP-negative individuals, 1.3% (20/1559) developed IA (1 UIA, 13 RA, 6 psoriatic arthritis); 75% (15/20) within 12 months. The relative risk for developing RA within 12 months in the anti-CCP-positive group was 66.8 (95% CI 32.2 to 138.4, p<0.001); for IA, it was 45.5 (95% CI 25.4 to 81.6, p<0.001)., Conclusions: Selecting individuals with new non-specific MSK symptoms without CS enriched the prevalence of anti-CCP positivity to 2.8%. Those who tested positive had a high risk of rapidly developing RA. The cost-effectiveness of this approach will need to be determined., Trial Registration Number: NCT02012764., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Chronic multiple-site joint pain (MSJP) is common in older people and associated with poor outcomes, yet under-researched. Our aim was to detail the clinical characteristics of people with MSJP and their utilisation of therapies., Methods: MSJP was defined as pain in at least one large joint and one other joint for >6 weeks in the last three months. A mixed community, primary and secondary care cohort of people >50 years old underwent detailed history and examination by a single clinician. Treatment utilisation was recorded comprehensively., Results: 201 adults were recruited, 82% women, mean age 63, BMI 31 kg/m(2). Median number of painful joints per patient was 6 (IQR 4-9; range 2-17); most common painful sites were knee (84%), lower back (62%) and shoulder (47%). 194/201 (96%) had an osteoarthritis (OA) diagnosis, 155/194 (80%) also had soft tissue pathology and 72% had back problems. 85% had OA at multiple sites. Upper and lower limb weakness was common (90 and 77% respectively). Lower limb weakness was significantly associated with obesity. Only 26% had received written information about their joints. Though 79% had attended physiotherapy, the majority (93%) had muscle weakness. Only 36 % of overweight participants had accessed weight-loss support. Half of those with foot pain had seen a podiatrist or used appliances. Multiple concurrent pharmacological therapies were used by 47%., Conclusion: MSJP represents a combination of OA, back pain and soft tissue disorders; muscle weakness is extremely common. Therapies appear underutilised in people with MJSP. Identifying the reasons for this should guide effective intervention research.

Biomechanical factors including occupational joint physical stressing and joint injury have been linked to spondyloarthritis. We explored such factors in ankylosing spondylitis (AS). A retrospective, online survey was developed alongside the UK National Ankylosing Spondylitis Society (NASS). Questions on early entheseal symptoms, potential precipitating trauma, sporting activity, and physiotherapy were asked. A total of 1026 patients responded with 44% recalling an instance of injury or trauma as a potential trigger for their AS. After symptom onset, 55% modified sporting activities and 28% reported that the initial AS recommended exercises exacerbated symptoms. Patients report physical trauma, exercise and physiotherapy as potential triggers for AS symptoms. These findings further support the experimental evidence for the role of biomechanical factors in disease.

Objectives: Immune age-related abnormalities may synergise with osteoarthritis (OA) pathology. We explored whether abnormalities in the blood immune cell composition are present in OA, beyond defects typically associated with ageing., Design: Blood was collected from 121 healthy controls (HC) and 114 OA patients. Synovial biopsies were obtained from another 52 OA patients. Flow cytometry was used to establish the frequencies of lineage subsets, naïve, memory and regulatory T and B-cells, cells with an abnormal phenotype related to inflammation (IRC) and memory-like CD8(+) T-cells. Multivariate analysis of covariance (MANCOVA) was used to determine whether the relative subset frequencies differed between HC and OA, controlling for age., Results: Expected histology and T/B-cell infiltration were observed. Following age adjusted analysis, we confirmed the lack of age association in HC for CD4(+), B, NK and NKT cells but a negative trend for CD8(+) T-cells. In OA, CD4(+) T-cell and B-cell frequency were lower compared to HC while CD8(+) T-cell frequencies were higher. CD8(+) memory-like cells were more likely to be found in OA (odds ratio = 15). Increased CD8(+) IRC frequencies were also present in OA. The relationship between age and CD4(+) or CD8(+) naïve T-cells in HC were changed in OA while the age relationships with memory cells were lost. The increase in CD4(+) Treg with age was also lost in OA. B-cells showed limited evidence of disturbance., Conclusions: Immune dysfunction may be present in OA beyond what appears related to ageing; this requires further investigation., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trabecular bone disconnection is an independent factor in age-related skeletal failure where real termini (ReTm; rare in youth) may cause weakness disproportionate to tissue loss, yet their structural contribution at vulnerable locations remains uncertain. ReTm (previously recorded at the iliac crest) were mapped in "normal" aged vertebral bodies (T11-L5 autopsy; 20 females, 10 males) and corresponding proximal femora (autopsy; 10 females). Results were compared with biomechanically failed femora from orthopaedic subjects aged >58 yr (osteoporosis OP, 10 females; osteoarthritis OA, 10 females). A novel direct 2D/3D histological method was applied to large, thick (300 μm) slices superficially silver-stained to separate ReTm (unstained) from apparent termini (planar artefacts, brown). Light microscope field co-ordinates enabled ReTm mapping and statistical testing relative to i) sex, ii) tissue sector and iii) slicing plane. In men ReTm populations were small and random while in women they were large and sector-specific. In vertebrae they clustered anterior/superior being rare posterior/inferior; in the femoral head they concentrated distal/superior and also near the fovea, being fewer distal/inferior. A distribution polarity was evident with 100% more ReTm observed transversely (i.e., on tensile-related cross struts) than longitudinally (i.e., on compression-related vertical struts). Their numbers rose in OP (BV/TV<14%, microCT) and in OA (BV/TV>14%), remaining polarised and sector-specific in OP only. Comparative experimentation by marrow elution of an OP animal model demonstrated "floating segments" as a possible outcome. Conclusions were supported statistically that trabecular disconnection "hotspots" at vulnerable locations are sex- and sector-specific, mainly transaxial, and subject to disease modulation., (Copyright © 2015. Published by Elsevier Inc.)

Objectives: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group., Methods: In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation., Findings: 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed)., Conclusions: In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention., Trial Registration Number: NCT02012764 at ClinicalTrials.gov., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Assessment of the synovium in patients with knee OA is of great potential value for clinical trials. Ultrasonography could provide this but few data exist on its ability to assess synovial response to therapies. The aim of this study was to examine whether US can detect synovial response to IA corticosteroid (IACS) therapy and to explore associations between synovial characteristics and symptoms., Methods: A total of 35 people with ACR radiographic knee OA were included, including those who required an injection of 80 mg of IA methylprednisolone. All participants completed a visual analogue scale for pain and underwent US of the knee at baseline, 1 and 4 weeks. Minimum clinically important improvement (MCII) in pain was ≥20 mm., Results: One week of data were available for 33 patients (19 received IACS and 14 others). Synovial thickness (ST) decreased in 16 IACS patients and 2 others [mean between-group difference 4.7 mm (95% CI 1.1, 8.2), P = 0.012]. Absolute reduction was not associated with absolute reduction in pain (r = 0.20, P = 0.289), but decreased ST was substantively associated with reduction in pain greater than or equal to the MCII (52.9% vs 23.1%, P = 0.098, φ = 0.30). The power Doppler score decreased in 13 IACS patients and 3 others {median change in IACS patients -1.0 [interquartile range (IQR) -5.0-0.0], others 0.0 [-0.3-1.3], P = 0.004}. Absolute changes in pain and power Doppler score were weakly associated (ρ = 0.36, P = 0.049) and a decreased power Doppler score was associated with reduction in pain greater than or equal to the MCII (64.3% vs 18.8%, P = 0.011, φ = 0.46)., Conclusion: Ultrasonography can detect short-term synovial response in knee OA. In particular, power Doppler score may be both responsive to and associated with pain, warranting further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lack of reproducibility is an ongoing problem in some areas of the biomedical sciences. Poor experimental design and a failure to engage with experienced statisticians at key stages in the design and analysis of experiments are two factors that contribute to this problem. The RIPOSTE (Reducing IrreProducibility in labOratory STudiEs) framework has been developed to support early and regular discussions between scientists and statisticians in order to improve the design, conduct and analysis of laboratory studies and, therefore, to reduce irreproducibility. This framework is intended for use during the early stages of a research project, when specific questions or hypotheses are proposed. The essential points within the framework are explained and illustrated using three examples (a medical equipment test, a macrophage study and a gene expression study). Sound study design minimises the possibility of bias being introduced into experiments and leads to higher quality research with more reproducible results.

Background: Bone erosion is one of the hallmarks of rheumatoid arthritis (RA), but also seen in other rheumatic diseases. The objective of this study was to determine the specificity of ultrasound (US)-detected bone erosions (including their size) in the classical 'target' joints for RA., Methods: Patients fulfilling the diagnostic criteria for RA, psoriatic arthritis, osteoarthritis or gout in addition to healthy volunteers were included. The following areas were examined by US: distal radius and ulna, 2nd, 3rd and 5th metacarpophalangeal (MCP), 2nd and 3rd proximal interphalangeal (PIP) and 1st and 5th metatarsophalangeal (MTP) joints. All joints were scanned in four quadrants using both semiquantitative (0-3) and quantitative (erosion diameter) scoring systems., Results: 310 subjects were recruited. The inter-reader and intrareader agreements were good to excellent. US-detected bone erosions were more frequent but not specific for RA (specificity 32.9% and sensitivity 91.4%). The presence of erosions with semiquantitative score ≥2 in four target joints (2nd, 5rd MCP, 5th MTP joints and distal ulna) was highly specific for RA (specificity 97.9% and sensitivity 41.4%). Size of erosion was found to be associated with RA. Erosions of any size in the 5th MTP joint were both specific and sensitive for RA (specificity 85.4% and sensitivity 68.6%)., Conclusions: The presence of US-detected erosions is not specific for RA. However, larger erosions in selected joints, especially 2nd and 5rd MCP, 5th MTP joints and distal ulna, were highly specific for and predictive of RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: To prospectively follow a cohort of elite young male professional soccer players with sequential symptom questionnaires and imaging of the anterior pelvis to determine the prevalence and severity of imaging findings., Methods: 34 male athletes (mean age 16.5 years) underwent clinical examination, history/symptom questionnaire, ultrasound and 1.5 T MRI of the anterior pelvis. Athletes then underwent annual questionnaire and ultrasound with MRI also performed every 18 months. Two experienced radiologists scored ultrasound (consensus) and MRI (independently) for abnormality including pubic bone, capsule and tendon oedema and scores correlated with symptoms and presence or absence of previous injuries., Results: Over 4 years the participants fell from 34 to 22 in number with no withdrawals due to groin injury. On study entry no athletes had undergone previous hip or pelvic surgery. On MRI pubic bone oedema, secondary cleft, capsule/tendon oedema and enhancement did not differ substantively between players with and without history of previous injury. κ Analysis for MRI scoring showed excellent agreement (0.84-0.96) for pubic bone marrow oedema, secondary cleft, capsule/tendon oedema and enhancement. On ultrasound inguinal wall motion and adductor tendinopathy did not differ substantively between players with and without history of previous injury. Stability of imaging assessments over time showed no consistent difference., Conclusions: Pubic bone marrow and parasymphyseal findings (cleft, capsule/tendon oedema) on MRI or inguinal canal ballooning on ultrasound were frequently found in asymptomatic athletes and did not predict injury or symptom development., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Early detection of osteoarthritis (OA) would increase the chances of effective intervention. We aimed to investigate which patient-reported activity is first associated with knee pain. We hypothesized that pain would occur first during activities requiring weight bearing and knee bending., Methods: Data were obtained from the Osteoarthritis Initiative (OAI), a multicenter, longitudinal prospective observational cohort of people who have or are at high risk of OA. Participants completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; Likert scale) annually for up to 7 years. Rasch analysis was used to rank the WOMAC pain questions (activities) in order of affirmation as the pain score increased from 0. For each total WOMAC score category (0-20) we selected 25 individuals at random based on their maximum score across all visits. Fit to the Rasch model was assessed in this subset; stability of question ranking over successive visits was confirmed in the full OAI., Results: WOMAC data on 4,673 people were included, with 491 selected for subset analysis. The subset data showed good fit to the Rasch model (χ(2) = 43.31, P = 0.332). In the full OAI, the "using stairs" question was the first to score points as the total pain score increased from 0 (baseline logit score ± 95% confidence interval -4.74 ± 0.07), then "walking" (-2.94 ± 0.07), "standing" (-2.65 ± 0.07), "lying/sitting" (-2.00 ± 0.08), and finally "in bed" (-1.32 ± 0.09). This ordering was consistent over successive visits., Conclusion: Knee pain is most likely to first appear during weight-bearing activities involving bending of the knee, such as using stairs. First appearance of this symptom may identify a group suitable for early intervention strategies., (© 2015 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Background: Radiographic measures of osteoarthritis (OA) are based upon two dimensional projection images. Active appearance modelling (AAM) of knee magnetic resonance imaging (MRI) enables accurate, 3D quantification of joint structures in large cohorts. This cross-sectional study explored the relationship between clinical characteristics, radiographic measures of OA and 3D bone area (tAB)., Methods: Clinical data and baseline paired radiographic and MRI data, from the medial compartment of one knee of 2588 participants were obtained from the NIH Osteoarthritis Initiative (OAI). The medial femur (MF) and tibia (MT) tAB were calculated using AAM. 'OA-attributable' tAB (OA-tAB) was calculated using data from regression models of tAB of knees without OA. Associations between OA-tAB and radiographic measures of OA were investigated using linear regression., Results: In univariable analyses, height, weight, and age in female knees without OA explained 43.1%, 32.1% and 0.1% of the MF tAB variance individually and 54.4% when included simultaneously in a multivariable model. Joint space width (JSW), osteophytes and sclerosis explained just 5.3%, 14.9% and 10.1% of the variance of MF OA-tAB individually and 17.4% when combined. Kellgren Lawrence (KL) grade explained approximately 20% of MF OA-tAB individually. Similar results were seen for MT OA-tAB., Conclusion: Height explained the majority of variance in tAB, confirming an allometric relationship between body and joint size. Radiographic measures of OA, derived from a single radiographic projection, accounted for only a small amount of variation in 3D knee OA-tAB. The additional structural information provided by 3D bone area may explain the lack of a substantive relationship with these radiographic OA measures., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Sensitive biomarkers are needed to understand synovial response to therapy in osteoarthritis (OA). Dynamic, contrast-enhanced magnetic resonance imaging (DCE MRI) provides quantitative, novel measures of synovial inflammation. This exploratory study examined DCE-assessed synovial response to intra-articular corticosteroid (IACS)., Methods: People with ACR clinical criteria OA knee underwent 3 T MRI pre- and 2 weeks post-IACS. Five MRI variables were assessed blindly: total synovial volume (semi-automated computer program), early enhancement rate (EER) and late enhancement ratio of the entire knee, synovial volume × late enhancement and a semi-quantitative (SQ) score (six sites scored 0-3). Clinical symptoms were assessed using pain visual analogue score (VAS) and WOMAC., Results: 13 participants (5 male, mean age 63, mean pain VAS 66 mm mean body mass index (BMI) 31.3 kg/m(2)) were included. The majority of MRIs demonstrated no change in SQ score although the DCE variables changed to some extent in all. There was generally a reduction in synovial volume ((Wilcoxon test) median (interquartile range (IQR)) reduction 14 cm(3) (-1, 29)), EER (0.2% (-0.3, 0.6)) and late enhancement ratio (8% (-0.5, 41)). Synovial volume × late enhancement ratio demonstrated a substantive reduction (2250 (-930, 5630)) as well as the largest effect size, r = 0.45. There was a median 26% reduction in EER in participants with good symptomatic response to IACS, contrasting with a 23% increase in those who responded poorly., Conclusions: DCE MRI may be more sensitive than a SQ score at detecting post-therapy synovial changes. The association between EER and symptomatic response to IACS may reflect a closer relation of this biomarker to synovial inflammation than with volumetric assessment., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis., Methods: In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52., Results: No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026)., Conclusions: In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy., Trial Registration Number: The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 (http://www.controlled-trials.com/ISRCTN55428162/EMPIRE). The full trial protocol can be obtained from the corresponding author.

Objective: The aim of this study was to identify the anatomical location of erosions at the MTP joints in patients with RA using high-resolution 3T MRI., Methods: In 24 patients with RA, the more symptomatic forefoot was imaged using 3T MRI. T1-weighted, intermediate-weighted and T2-weighted fat-suppressed sequences were acquired through the MTP joints, together with three-dimensional volumetric interpolated breath-hold examination (3D VIBE) and T1-weighted fat-suppressed post-gadolinium contrast sequences. Images were scored for bone erosion in the distal and proximal part of the MTP joints using the RA MRI scoring (RAMRIS) system. The base of the proximal phalanx and the head of the metatarsal were divided into quadrants to determine the location of erosions (octants) in the dorsal-medial, dorsal-lateral, plantar-medial and plantar-lateral regions., Results: Seventeen females and seven males with a mean age of 55.5 years and disease duration of 10.6 years (range 0.6-36) were included. Eighteen patients were RF positive, the mean 44-joint DAS for CRP and ESR (DAS44CRP and DAS44ESR) were 2.5 (s.d. 0.8) and 2.6 (s.d. 0.9), respectively. In this cohort of patients with RA, irrespective of MTP joint location, octants located in the proximal part (metatarsal) of the joint and the plantar aspect of the joint were more eroded., Conclusion: This is the first study to report the anatomical location of erosions at the MTP joints in patients with RA. We noted that erosions were more commonly seen on the plantar aspect of the metatarsal head in RA, supporting the hypothesis of a relationship between biomechanical demands and bone changes in the forefoot.

Objectives: Bisphosphonates have some reported beneficial effects in treating osteoarthritis (OA). This study examined the effects of bisphosphonate use on symptoms and structural progression of knee OA in participants from the NIH Osteoarthritis Initiative cohort., Methods: People with typical OA trial entry criteria (KL2/3, minimum joint space width 2.5-5.0 mm and pain ≥4 on a numeric rating scale) were classified as bisphosphonate users (≥3 of the 5 years; n=55) or non-users (no use in the preceding 5 years or during follow-up; n=268). Annual data over 4 years were analysed using linear mixed modelling and generalised estimating equations., Results: Bisphosphonate compliance was 85% at year 1, reducing to 76% by year 4. Numeric rating scale pain scores were significantly reduced among bisphosphonate users at years 2 and 3 (year 3, -0.9 vs -2.2, p=0.004), though not year 4, after adjustment for baseline pain and analgesic use. Differences in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and disability scores did not reach statistical significance at any time point. There was a trend to less joint space narrowing in bisphosphonate users over time (year 4, 0.51 vs 0.29 mm; p=0.06)., Conclusions: Significant reduction in numeric rating scale pain was observed in the first 3 years with bisphosphonate use; diminution of effects by year 4 may reflect reduced compliance. Differences in results obtained using numeric rating scale and WOMAC may reflect different constructs measured by these tools. The beneficial trend on structural progression should be considered in terms of the sample size.

Objective: Arthritis activity assessments in psoriatic arthritis (PsA) have traditionally relied on tender and swollen joint counts, but in rheumatoid arthritis, multiple studies have demonstrated subclinical inflammation using modern imaging. The aim of this study was to compare clinical examination and ultrasound (US) findings in an early PsA cohort., Methods: Forty-nine disease-modifying antirheumatic drug-naive patients with recent-onset PsA (median disease duration 10 months) underwent gray-scale (GS) and power Doppler (PD) US of 40 joints plus tender and swollen joint counts of 68/66 joints. GS and PD were scored on a 0-3 semiquantitative scale for each joint. Clinically active joints were defined as tender and/or swollen and US active joints were defined as a GS score ≥2 and/or a PD score ≥1., Results: The most common sites for subclinical synovitis were the wrist (30.6%), knee (21.4%), metatarsophalangeal (MTP) joints (26.5-33.7%), and metacarpophalangeal joints (10.2-19.4%). Excluding MTP joints and ankles, 37 (75.5%) of 49 patients had subclinical synovitis with a median of 3 (interquartile range [IQR] 1-4) joints involved. In contrast, clinical overestimation of synovitis occurred most commonly at the shoulder (38%) and ankle (28.6%). Twelve of 49 patients were classified clinically as having oligoarthritis; of these, subclinical synovitis identified 8 (75%) as having polyarthritis with an increase in their median joint count from 3 (IQR 1-4) to 6 (IQR 5-7)., Conclusion: This study has demonstrated that subclinical synovitis, as identified by US, is very common in early PsA and led to the majority of oligoarthritis patients being reclassified as having polyarthritis. Further research is required into the relationship of such subclinical synovitis to structural progression., (© 2014 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objectives: To review the literature in order to estimate how many previously unknown thoracic aortic aneurysms (TAAs) and thoracic aortic dilatations (TADs) might be detected by systematic, cross-sectional aortic imaging of patients with giant cell arteritis (GCA)., Methods: A systematic literature review was performed using Ovid Medline, Embase and the Cochrane Library. Studies potentially relevant to TAA/TAD were evaluated by two authors independently for relevance, bias and heterogeneity. Meta-analysis was performed using a random-effects model to estimate pooled prevalence., Results: Two analyses of routinely collected administrative data suggested a threefold risk of TAA/dissection in GCA compared with controls. In GCA cohorts without systematic imaging, 2-8% had TAA. In the two best-reported studies, aneurysm dissection/rupture occurred in 1% and 6% of GCA cases. Aortic imaging studies had a variety of TAA/TAD definitions, imaging methods and time points. There were limited data on age-matched controls. Three studies suggested that male sex may be a risk factor for TAA/TAD in GCA. On average, five to ten patients with GCA would need aortic imaging to detect one previously unknown TAA/TAD., Conclusions: The data support an association between GCA and TAA/TAD compared with age-matched controls, but the true relative risk, and the time course of that risk, remains unclear. It is also unclear whether chest radiography is a sufficiently sensitive screening tool. Clinicians should retain a high index of suspicion for aortic pathology in patients with GCA. Before ordering imaging, clinicians should consider whether, and how, detecting aortic pathology would affect a patient's management.

Objectives: In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction., Methods: In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50., Results: The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen., Conclusions: In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

Objective: To compare the effectiveness of a physiotherapy programme with a control treatment of advice and education in patients with neurogenic claudication symptoms., Design: Pragmatic randomised controlled clinical trial., Setting: Primary care-based musculoskeletal service., Patients: Adults aged 50 or over with neurogenic claudication symptoms causing limitation of walking., Interventions: Condition-specific home exercises combined with advice and education, or advice and education alone., Main Outcome Measures: The primary outcome was the difference in improvement of symptom severity scores on the Swiss Spinal Stenosis Scale at eight weeks. Secondary outcomes included measures of physical function, pain and general well-being at eight weeks and 12 months., Results: There was no significant difference between groups in the Swiss Spinal Stenosis symptom severity scale at eight weeks (t = 0.47, p = 0.643): mean change (SD) control group -0.18 (0.47), treatment group -0.10 (0.66), difference (95% CI) 0.08 (-0.19, 0.35); baseline-adjusted difference 0.06 (-0.19, 0.31)]. An unplanned subgroup analysis suggested that for patients with the top 25% of baseline symptom severity scores, the physiotherapy exercise programme resulted in an improvement in the primary outcome, and modest but consistently better secondary outcomes at both time-points compared to the control group. The effectiveness in different subgroups requires further direct evaluation., Conclusions: In the treatment of patients with neurogenic claudication symptoms, a physiotherapist-prescribed home exercise programme is no more effective than advice and education., Ethical Approval: The study was approved by Leeds Central Ethics Committee and informed consent was given by all participating patients., Copyright: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where-ever it may be located; and, vi) licence any third party to do any or all of the above., Trial Registration: ISRCTN 78288224 - doi10.1186/ISRCTN35836727; UKCRN 4814.

Objective: To perform a cost-effectiveness analysis of subacromial corticosteroid injection combined with exercise compared with exercise alone in patients with moderate to severe shoulder pain from subacromial impingement syndrome., Methods: A within-trial cost-effectiveness analysis with 232 patients randomized to physiotherapy-led injection combined with exercise (n = 115) or exercise alone (n = 117). The analysis was from a health care perspective with 24-week follow-up. Resource use information was collected from all patients on interventions, medication, primary and secondary care contacts, private health care use and over-the-counter purchases. The measure of outcome was quality-adjusted life years (QALYs), calculated from EQ-5D responses at baseline and three further time points. An incremental cost-effectiveness analysis was conducted., Results: Mean per patient NHS costs (£255 vs £297) and overall health care costs (£261 vs £318) were lower in the injection plus exercise arm, but this difference was not statistically significant. Total QALYs gained were very similar in the two trial arms (0.3514 vs 0.3494 QALYs), although slightly higher in the injection plus exercise arm, indicating that injection plus exercise may be the dominant treatment option. At a willingness to pay of £20,000 per additional QALY gained, there was a 61% probability that injection plus exercise was the most cost-effective option., Conclusion: Injection plus exercise delivered by therapists may be a cost-effective use of resources compared with exercise alone and lead to lower health care costs and less time off work., Trial Registration: International Standard Randomised Controlled Trial Number Register, http://www.controlled-trials.com/isrctn/, ISRCT 25817033.

Objective: This study used high-resolution PET to explore the pattern of DIP joint bone metabolism to test the hypothesis that the nail was functionally integrated with the bone, based on patterns of distal phalange (DP) bone metabolism in PsA compared with OA and normal joints., Methods: A total of 234 DIP joints were scanned in 30 subjects (10 PsA, 10 OA, 10 healthy control) with [18F]fluoride using the quad-high-density avalanche chamber nano PET scanner. The images were assessed blinded to diagnosis and symptoms for site and intensity of increased [18F]fluoride uptake., Results: [18F]fluoride uptake in the DP was strong relative to the intermediate phalange in both PsA and OA. In PsA there was a trend for uptake to occur in a diffuse pattern involving the entire DP. There was also greater uptake at the enthesis, the periosteum and at the tufts of the DP of PsA compared with OA. In OA, uptake was greatest in the subchondral region adjacent to known sites of osteophytosis and erosions. Both PsA and OA joints with uptake at the subchondral or periosteal bone are likely to be more symptomatic., Conclusion: This exploratory study suggested diffuse increased bone metabolism involving the entire DP, periosteum and entheses, especially in PsA. The subchondral bone and periosteum at the DP have large concentrations of enthesis attachments, including attachments from the nail, supporting the concept of an integrated nail and joint apparatus leading to a wide area of abnormal bone metabolism in PsA.