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1.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Background
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Methods
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
Findings
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Interpretation
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
doi:10.1016/S2213-8587(16)00044-9
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
2.  Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis 
PLoS Genetics  2016;12(10):e1006260.
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
Author Summary
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability in the western society affecting millions of people. OA is a degenerative joint disease characterized by changes in all joint tissues, including cartilage, bone and synovium, causing chronic pain and loss of function. There are no effective therapeutic treatments available for OA and therefore finding novel biological pathways through genetic association studies can open up new treatment options. The number of known DNA variants associated with OA-risk is limited.
To identify new loci, we have performed a Genome Wide Association Study meta-analysis on cartilage thickness, one of the joint tissues affected in OA in a total sample of more than 20,000 individuals from twelve cohorts. This analysis revealed six variants associated with cartilage thickness, four of these being novel associations, including TGFA as the most prominent one. A systematic prioritization for underlying causal genes, using diverse lines of evidence, highlighted genes underlying the disease associations, including TGFA, RUNX2 and PIK3R1. Large scale exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies
doi:10.1371/journal.pgen.1006260
PMCID: PMC5049763  PMID: 27701424
3.  Are there three main subgroups within the patellofemoral pain population? A detailed characterisation study of 127 patients to help develop targeted intervention (TIPPs) 
British Journal of Sports Medicine  2016;50(14):873-880.
Background
Current multimodal approaches for the management of non-specific patellofemoral pain are not optimal, however, targeted intervention for subgroups could improve patient outcomes. This study explores whether subgrouping of non-specific patellofemoral pain patients, using a series of low cost simple clinical tests, is possible.
Method
The exclusivity and clinical importance of potential subgroups was assessed by applying à priori test thresholds (1 SD) from seven clinical tests in a sample of adult patients with non-specific patellofemoral pain. Hierarchical clustering and latent profile analysis, were used to gain additional insights into subgroups using data from the same clinical tests.
Results
130 participants were recruited, 127 had complete data: 84 (66%) female, mean age 26 years (SD 5.7) and mean body mass index 25.4 (SD 5.83), median (IQR) time between onset of pain and assessment was 24 (7–60) months. Potential subgroups defined by the à priori test thresholds were not mutually exclusive and patients frequently fell into multiple subgroups. Using hierarchical clustering and latent profile analysis three subgroups were identified using 6 of the 7 clinical tests. These subgroups were given the following nomenclature: (1) ‘strong’, (2) ‘weak and tighter’ and (3) ‘weak and pronated foot’.
Conclusions
We conclude that three subgroups of patellofemoral patients may exist based on the results of six clinical tests which are feasible to perform in routine clinical practice. Further research is needed to validate these findings in other data sets and, if supported by external validation, to see if targeted interventions for these subgroups improve patient outcomes.
doi:10.1136/bjsports-2015-094792
PMCID: PMC4975826  PMID: 26834185
Physiotherapy; Knee
4.  A pilot investigation of the prevalence of US-detectable forefoot joint pathology and reported foot-related disability in participants with systemic lupus erythematosus 
Background
The main aim of this study was to determine the prevalence of US-detectable forefoot bursae, metatarsophalangeal (MTP) joint and metacarpophalangeal (MCP) joint synovial hypertrophy (SH), Power Doppler (PD) signal or erosion in participants with systemic lupus erythematosus (SLE). A secondary aim was to determine the strength of potential association between patient reported foot-related disability and US-detected forefoot bursae, MTP joint SH, PD signal or erosion in participants with SLE.
Method
A cross-sectional observational study of 20 participants with SLE was completed to determine the prevalence of US-detected forefoot bursal, MTP and MCP joint pathology. Patient-reported foot-related impairment and activity limitation (accumulatively referred to as disability) were also recorded. Spearmans’ Rank Correlation analyses were completed to determine the potential strength of association between US-detected pathology and patient report disability.
Results
The prevalence of MTP joint SH and PD was 80 % (16/20) and 10 % (2/20), respectively. The prevalence of MCP joint SH and PD was 60 % (12/20) and 30 % (6/20) respectively. A significant association was noted between PD scores for the MTP joints and MCP joints (r = 0.556; p = 0.011) although this was not demonstrated for SH scores (r = 0.176; p = 0.459). Significant associations between forefoot bursal prevalence and MTP joint PD were noted (r = 0.467; p = 0.038). The prevalence of bursae and bursal PD (grade 2 or above) was 100 % (20/20) and 10 % (2/20), respectively. Moderate foot-related impairment and activity limitation was reported by 95 and 85 % of participants respectively.
Conclusion
This pilot study suggests that US-detected MTP, MCP joint and forefoot bursal abnormalities may be prevalent in participants with SLE and they may experience a moderate level of foot-related disability. Further research is required to substantiate these preliminary findings.
doi:10.1186/s13047-016-0158-1
PMCID: PMC4969688  PMID: 27486482
Lupus erythematosus; Systemic; Forefoot; Human; Joints; Bursa; Synovial; Ultrasonography
5.  Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis 
Objective
Genetic polymorphisms within the HLA region explain only a modest proportion of anti–cyclic citrullinated peptide (anti‐CCP)–negative rheumatoid arthritis (RA) heritability. However, few non‐HLA markers have been identified so far. This study was undertaken to replicate the associations of anti‐CCP–negative RA with non‐HLA genetic polymorphisms demonstrated in a previous study.
Methods
The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune‐related regions in 3,339 anti‐CCP–negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case–control replication study of the anti‐CCP–negative markers with the strongest associations in that discovery study, in an independent cohort of anti‐CCP–negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome‐wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel.
Results
After genotyping and imputation quality control procedures, data were available for 15 non‐HLA single‐nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta‐analysis odds ratio [OR] 0.80; P = 2.8 × 10−13) and BLK (OR 1.13; P = 7.0 × 10−6) and identified new and specific markers of anti‐CCP–negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10−6] and NFIA [OR 0.85; P = 2.5 × 10−6]). Neither of these loci is associated with other common, complex autoimmune diseases.
Conclusion
Anti‐CCP–negative RA and anti‐CCP–positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti‐CCP–negative RA.
doi:10.1002/art.39619
PMCID: PMC4924598  PMID: 26895230
6.  An increased rate of falling leads to a rise in fracture risk in postmenopausal women with self-reported osteoarthritis: a prospective multinational cohort study (GLOW) 
Annals of the rheumatic diseases  2012;72(6):911-917.
Objective
Patients with osteoarthritis have increased bone mass, but no decrease in fractures. We studied the association between self-reported osteoarthritis and incident falls and fractures in postmenopausal women.
Methods
GLOW is a prospective, multinational cohort of 60 393 non-institutionalised women aged ≥55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as osteoarthritic if they answered yes to the question “Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?”, and this was validated against primary care records. Information on incident falls, fractures, and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status.
Results
Of 51 386 women followed for a median of 2.9 (interquartile range 2.1 to 3.0) years, 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls: HR 1.06 (95% CI 0.98 to 1.15; p=0.13).
Conclusion
Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than osteoarthritis-free peers. Our data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.
doi:10.1136/annrheumdis-2012-201451
PMCID: PMC4886333  PMID: 22730372
Osteoporosis; Osteoarthritis; Fractures; Bone; Accidental Falls; Epidemiology
7.  Investigation of Association Between Hip Osteoarthritis Susceptibility Loci and Radiographic Proximal Femur Shape 
Objective
To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.
Methods
We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome‐wide association study. We built 3 SSMs capturing the shape variation of the OA‐unaffected proximal femur in the entire mixed‐sex cohort and for male/female‐stratified cohorts. We selected 41 candidate single‐nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype–phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.
Results
The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed‐sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed‐sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.
Conclusion
These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
doi:10.1002/art.39186
PMCID: PMC4864451  PMID: 25939412
8.  The College of Podiatry Annual Conference 2015: meeting abstracts 
Tong, Jasper W. K. | Kong, Veni P. | Sze, Lily | Gale, Susie | Veto, John | McArdle, Carla | Tunprasert, Thanaporn | Bradley, Victoria | Strike, Siobhan | Tunprasert, Thanaporn | Bradley, Victoria | Strike, Siobhan | Ashford, Robert | Naemi, Roozbeth | Chocklingam, Nachiappan | de Blasc, Xavi | Farndon, Lisa | Robinson, Vicki | Nicholls, Emily | Birch, Tabitha | Birch, Ivan | Otter, Simon | Kumar, Sunil | Gow, Peter | Dalbeth, Nicola | Corkill, Michael | Davies, Kevin | Panthakalam, Sam | Rohan, Maheswaran | Rome, Keith | Egan, Chloe | Chandler, Lisa | Tehan, Peta | Chuter, Vivienne | Sonter, Jennifer | Lanting, Sean | Hicks, Lorna | Joyce, Christopher | Watterson, David | McIntosh, Caroline | Joyce, Christopher | Roberts, Nigel | Forss, Jacqueline | Charalambous, Chrystalla | Kirby, Jack | Ojo, Oluwakemi | Forss, Jacqueline | Caukill, Sarah | Capon, Jacqueline | Fong, Radiance | Loy, Louis | Diment, Matthew | Murray, Madeleine | Ellis, Mairghread | McArdle, Carla | Tehan, Peta | Chuter, Vivienne | Oldmeadow, Christopher | Carey, Nicola | Stenner, Karen | Gage, Heather | Brown, Jane | Williams, Peter | Otter, Simon | Moore, Ann | Edwards, Jude | Mold, Freda | Courtenay, Molly | Tehan, Peta | Bray, Alan | Chuter, Vivienne | Hindmoor, Pamela | Gwynne, Craig | Curran, Sarah | Bridgen, Andy | Fairhurst, Caroline | Adamson, Joy | Martin, Belen Corbacho | Cockayne, Sarah | Hewitt, Catherine | Hicks, Kate | Keenan, Anne-Maree | Loughrey-Green, Lorraine | Menz, Hylton | Redmond, Anthony | Rodgers, Sara | Watson, Jude | Torgerson, David | Hull, Robin | Lamb, Sarah | McIntosh, Caroline | Vernon, Wesley | Farndon, Lisa | Loughrey-Green, Lorraine | Cockayne, Sarah | Redmond, Anthony | Keenan, Anne-Maree | Rodgers, Sara | Farndon, Lisa | Vernon, Wesley | Torgerson, David | Fairhurst, Caroline | Watson, Jude | Menz, Hylton | Lamb, Sarah | Hull, Robin | Wylie, Gavin | Young, Zoe | Williams, Brian | Sullivan, Frank | Menz, Hylton | Ogston, Simon | Morris, Jacqui | Bowen, Cathy | Kunkel, Dorit | Cole, Mark | Donovan-Hall, Margaret | Pickering, Ruth | Burnett, Malcolm | Bader, Dan | Robison, Judy | Mamode, Louis | Ashburn, Ann | McQueen, Peter | Daniels, Maxine | Doherty, Michael | Arden, Nigel | Bowen, Cathy | Dando, Charlotte | Cherry, Lindsey | Bowen, Cathy | Stefanou, Nichola | Cockayne, Sarah | Adamson, Joy | Fairhurst, Caroline | Hewitt, Catherine | Keenan, Anne-Maree | Lamb, Sally | Loughrey-Green, Lorraine | McIntosh, Caroline | Menz, Hylton | Redmond, Anthony | Rodgers, Sara | Vernon, Wesley | Watson, Jude | Farndon, Lisa | Corbacho, Belen | Hull, Robin | Torgerson, David | Alcacer-Pitarch, Begonya | Redmond, Anthony | Buch, Maya | Keenan, Anne-Maree
Table of content
P3 Medial longitudinal arch development of school children
Jasper W.K. Tong, Veni P. Kong
P4 Is measuring the subtalar joint reliable?
Lily Sze, Susie Gale, John Veto, Carla McArdle
P5 Comparison of turning gait biomechanics between able-bodied and unilateral transtibial amputee participants
Thanaporn Tunprasert, Victoria Bradley, Siobhan Strike
P6 Comparison of walking gait biomechanics between able-bodied and unilateral transtibial amputee participants using a new model of energy-storage-and-return (ESAR) prosthetic
Thanaporn Tunprasert, Victoria Bradley, Siobhan Strike
P7 An observational study of in-shoe plantar and dorsal pressures of skilled downhill skiers on a dry ski slope
Robert Ashford, Roozbeth Naemi, Nachiappan Chocklingam, Xavi de Blasc
P8 If the shoe fits: a footwear choice toolkit informed by social science methodologies
Lisa Farndon, Vicki Robinson, Emily Nicholls
P9 The identification of emotions from gait
Tabitha Birch, Ivan Birch
P11 Experience of foot problems in patients with systemic lupus erythematosus
Simon Otter, Sunil Kumar, Peter Gow, Nicola Dalbeth, Michael Corkill, Kevin Davies, Sam Panthakalam, Maheswaran Rohan, Keith Rome
P14 Negative pressure wound therapy for the management of foot wounds in the diabetic population: a review of the literature
Chloe Egan, Lisa Chandler
P15 Lower limb vascular assessment in diabetes: a multifaceted assessment of objective screening techniques
Peta Tehan, Vivienne Chuter, Jennifer Sonter, Sean Lanting
P16 Improving outcomes for diabetes foot complications
Lorna Hicks
P17 Acupuncture… an alternative or adjunctive treatment option for diabetes-related neuropathic pain?
Christopher Joyce, David Watterson, Caroline McIntosh
P18 “My back is in agony” – A cross-sectional study into the relationship between musculoskeletal complaints and a whole body postural risk assessment in podiatry students
Christopher Joyce, Nigel Roberts
P19 Swabs of the treatment couches: Does the material type and texture of podiatric treatment couches increase microorganism contamination?
Jacqueline Forss, Chrystalla Charalambous, Jack Kirby, Oluwakemi Ojo
P20 Does increased exudate viscosity effect the absorption rate of exudate into four different wound dressings?
Jacqueline Forss, Sarah Caukill, Jacqueline Capon, Radiance Fong, Louis Loy
P21 An investigation into the microbial load of a 40 °C and 60 °C wash
Matthew Diment, Madeleine Murray, Mairghread Ellis, Carla McArdle
P23 The sensitivity and specificity of the toe brachial index in detecting peripheral arterial disease: a systematic review and meta-analysis
Peta Tehan, Vivienne Chuter, Christopher Oldmeadow
P24 Medicines management activities and non-medical prescribing within podiatry and physiotherapy: an integrative review of the literature
Nicola Carey, Karen Stenner, Heather Gage, Jane Brown, Peter Williams, Simon Otter, Ann Moore, Jude Edwards, Freda Mold, Molly Courtenay
A7.2 Non-invasive vascular assessment in the foot with Diabetes: Diagnostic accuracy of ankle brachial index, toe brachial index and continuous wave Doppler
Peta Tehan, Alan Bray, Vivienne Chuter
A7.5 The efficacy of dressings on post nail surgery phenolised wounds
Pamela Hindmoor
B7.1 Cross-sectional study investigating the role of proximal and distal factors in the development of patellofemoral joint pain
Craig Gwynne, Sarah Curran
B7.2 Podiatrist’s interpretation and use of evidence in MSK practice
Andy Bridgen
B7.4 Predictors of falling in older podiatry patients – findings from the REFORM study
Caroline Fairhurst, Dr Joy Adamson, Belen Corbacho Martin, Sarah Cockayne, Prof Catherine Hewitt, Kate Hicks, Anne-Maree Keenan, Lorraine Loughrey-Green, Hylton Menz, Anthony Redmond, Sara Rodgers, Jude Watson, David Torgerson, Robin Hull, Sarah Lamb, Caroline McIntosh, Wesley Vernon, Lisa Farndon
B7.5 The REFORM study: Insole preference, requirements and compliance of podiatry patient’s aged 65 and over and at risk of falling
Lorraine Loughrey-Green, Sarah Cockayne, Anthony Redmond, Anne-Maree Keenan, Sara Rodgers, Lisa Farndon, Wesley Vernon, David Torgerson, Caroline Fairhurst, Jude Watson, Hylton Menz, Sarah Lamb, Robin Hull
B7.6 A podiatry intervention to reduce falls in care home residents is feasible and demonstrates benefits: results from PIRFECT, a feasibility randomised controlled trial
Gavin Wylie, Zoe Young, Brian Williams, Frank Sullivan, Hylton Menz, Simon Ogston, Jacqui Morris
C7.1 A survey exploring footwear habits in people with stroke and people with Parkinson’s
Cathy Bowen, Dorit Kunkel, Mark Cole, Margaret Donovan-Hall, Ruth Pickering, Malcolm Burnett, Dan Bader, Judy Robison, Louis Mamode, Ann Ashburn
C7.2 Painful foot osteoarthritis; a common symptom in a common pathology?
Peter McQueen, Maxine Daniels, Michael Doherty, Nigel Arden, Cathy Bowen
C7.4 Clinical diagnosis of symptomatic forefoot neuroma in the general population: Delphi based recommendations
Charlotte Dando, Lindsey Cherry, Cathy Bowen
C7.5 The development and implementation of a Clinical Quality Improvement Framework suitable for use in community services
Nichola Stefanou
C7.6 The REFORM study - methodological considerations in running a cohort randomised controlled trial within a podiatry patient caseload
Sarah Cockayne, Joy Adamson, Caroline Fairhurst, Catherine Hewitt, Anne-Maree Keenan, Sally Lamb, Lorraine Loughrey-Green, Caroline McIntosh, Hylton Menz, Anthony Redmond, Sara Rodgers, Wesley Vernon, Jude Watson, Lisa Farndon, Belen Corbacho, Robin Hull, David Torgerson
A31 Jewel in the crown: Exploring the factors contributing to the development and impact of foot problems in Systemic Sclerosis (SSc)
Begonya Alcacer-Pitarch, Anthony Redmond, Maya Buch, Anne-Maree Keenan
doi:10.1186/s13047-016-0141-x
PMCID: PMC4896266
9.  Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group 
Rheumatology (Oxford, England)  2016;55(8):1394-1402.
Objective. Treatment of OA by stratifying for commonly used and novel therapies will likely improve the range of effective therapy options and their rational deployment in this undertreated, chronic disease. In order to develop appropriate datasets for conducting post hoc analyses to inform approaches to stratification for OA, our aim was to develop recommendations on the minimum data that should be recorded at baseline in all future OA interventional and observational studies.
Methods. An Arthritis Research UK study group comprised of 32 experts used a Delphi-style approach supported by a literature review of systematic reviews to come to a consensus on core data collection for OA studies.
Results. Thirty-five systematic reviews were used as the basis for the consensus group discussion. For studies with a primary structural endpoint, core domains for collection were defined as BMI, age, gender, racial origin, comorbidities, baseline OA pain, pain in other joints and occupation. In addition to the items generalizable to all anatomical sites, joint-specific domains included radiographic measures, surgical history and anatomical factors, including alignment. To demonstrate clinical relevance for symptom studies, the collection of mental health score, self-efficacy and depression scales were advised in addition to the above.
Conclusions. Currently it is not possible to stratify patients with OA into therapeutic groups. A list of core and optional data to be collected in all OA interventional and observational studies was developed, providing a basis for future analyses to identify predictors of progression or response to treatment.
doi:10.1093/rheumatology/kew201
PMCID: PMC4957675  PMID: 27084310
osteoarthritis; clinical trials; stratification; prognosis; personalized medicine
10.  Serum cartilage oligomeric matrix protein and development of radiographic and painful knee osteoarthritis. A community-based cohort of middle-aged women 
Biomarkers  2015;20(8):557-564.
Abstract
Context and objective: We evaluated the predictive value of serum cartilage oligomeric matrix protein (sCOMP) levels over 20 years on the development of radiographic (RKOA) and painful knee osteoarthritis (KOA) in a longitudinal cohort of middle-aged women.
Materials and methods: Five hundred and ninety-three women with no baseline KOA underwent 5-year knee radiographs over 20-years and were asked about knee pain a month before each assessment. A repeated measures logistic regression model was used where the outcomes were recorded at 5, 10, 15 and 20-years follow-up.
Results: The highest quartile of sCOMP was associated with increased risk of RKOA with overall OR of 1.97 (95% CI: 1.33–2.91) over 20 years when compared with the lowest sCOMP quartile. The association with painful KOA was similar and also independent, but only when the fourth and third sCOMP quartiles were compared.
Discussion and conclusion: This study demonstrates that sCOMP levels are predictive of subsequent structural changes and incidence of painful KOA, independently of age and BMI.
doi:10.3109/1354750X.2015.1105498
PMCID: PMC4819573  PMID: 26848781
Cohort; COMP; epidemiology; knee; osteoarthritis
11.  Adipokines as potential prognostic biomarkers in patients with acute knee injury 
Biomarkers  2015;20(8):519-525.
Abstract
This review considers adipokines as predictive biomarkers for early onset post-traumatic knee osteoarthritis (KOA). Serum concentrations of leptin and resistin can predict radiographic changes and are elevated in early KOA, with higher leptin concentrations independently associated with more severe knee changes. Plasma concentrations of resistin are chronically elevated after injury. Leptin, resistin, chemerin and vistfatin induce catabolic enzymes associated with cartilage degeneration. Available literature on adipokines in post-traumatic KOA pathogenesis suggests that they could contribute to risk prediction of early onset post-traumatic KOA. Further research is needed to further understand the association between adipokines, synovitis and long-term outcomes in this population.
doi:10.3109/1354750X.2014.948914
PMCID: PMC4819580  PMID: 26006054
Bone repair; cytokines; growth factors; inflammatory mediators; obesity/diabetes; osteoarthritis
12.  Low maternal vitamin D status and fetal bone development: cohort study 
Recent findings suggest that maternal vitamin D insufficiency during pregnancy has consequences for the offspring’s bone health in later life. To investigate whether maternal vitamin D insufficiency affects fetal femur growth in ways similar to those seen in childhood rickets, and study the timing during gestation of any effect of maternal vitamin D status, we studied 424 pregnant women within a prospective longitudinal study of maternal nutrition and lifestyle before and during pregnancy (the Southampton Women’s Survey). Using high-resolution 3D ultrasound we measured fetal femur length and distal metaphyseal cross-sectional area, together with the ratio of femoral metaphyseal cross sectional area to femur length (“femoral splaying index”). Lower maternal 25-hydroxyvitamin vitamin D concentration was not related to fetal femur length, but was associated with greater femoral metaphyseal cross-sectional area and a higher femoral splaying index at 19 weeks gestation (r=−0.16, (95%CI:−0.25 to −0.06) and r=−0.17, (95%CI: −0.26 to −0.07), respectively) and at 34 weeks gestation (r=−0.10, 95%CI:−0.20 to 0.00) and r=−0.11, (95%CI: −0.21 to −0.01), respectively). Three groups of women were identified with 25-hydroxyvitamin vitamin D concentrations that were sufficient/borderline (>50 nmol/L, 63.4%), insufficient (25-50 nmol/L, 30.7%) and deficient (≤25 nmol/L, 5.9%). Across these groups, the geometric mean femoral splaying indices at 19 weeks gestation increased from 0.074 (sufficient/borderline) to 0.078 (insufficient) and 0.084 (deficient). Our observations suggest that maternal vitamin D insufficiency can influence fetal femoral development as early as 19 weeks gestation. This suggests that measures to improve maternal vitamin D status should be instituted in early pregnancy.
doi:10.1359/jbmr.090701
PMCID: PMC4768344  PMID: 19580464
vitamin D; fetus; developmental origins; osteoporosis; three-dimensional ultrasound
13.  Clinical effectiveness of orthogeriatric and fracture liaison service models of care for hip fracture patients: population-based longitudinal study 
Age and Ageing  2016;45(2):236-242.
Objectives: to evaluate orthogeriatric and nurse-led fracture liaison service (FLS) models of post-hip fracture care in terms of impact on mortality (30 days and 1 year) and second hip fracture (2 years).
Setting: Hospital Episode Statistics database linked to Office for National Statistics mortality records for 11 acute hospitals in a region of England.
Population: patients aged over 60 years admitted for a primary hip fracture from 2003 to 2013.
Methods: each hospital was analysed separately and acted as its own control in a before–after time-series design in which the appointment of an orthogeriatrician or set-up/expansion of an FLS was evaluated. Multivariable Cox regression (mortality) and competing risk survival models (second hip fracture) were used. Fixed effects meta-analysis was used to pool estimates of impact for interventions of the same type.
Results: of 33,152 primary hip fracture patients, 1,288 sustained a second hip fracture within 2 years (age and sex standardised proportion of 4.2%). 3,033 primary hip fracture patients died within 30 days and 9,662 died within 1 year (age and sex standardised proportion of 9.5% and 29.8%, respectively). The estimated impact of introducing an orthogeriatrician on 30-day and 1-year mortality was hazard ratio (HR) = 0.73 (95% CI: 0.65–0.82) and HR = 0.81 (CI: 0.75–0.87), respectively. Following an FLS, these associations were as follows: HR = 0.80 (95% CI: 0.71–0.91) and HR = 0.84 (0.77–0.93). There was no significant impact on time to second hip fracture.
Conclusions: the introduction and/or expansion of orthogeriatric and FLS models of post-hip fracture care has a beneficial effect on subsequent mortality. No evidence for a reduction in second hip fracture rate was found.
doi:10.1093/ageing/afv204
PMCID: PMC4776625  PMID: 26802076
epidemiology; hip fracture; fracture liaison service; orthogeriatrician; osteoporosis; older people
14.  Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib 
Objectives
To compare the efficacy and safety of chondroitin sulfate plus glucosamine hydrochloride (CS+GH) versus celecoxib in patients with knee osteoarthritis and severe pain.
Methods
Double-blind Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) conducted in France, Germany, Poland and Spain evaluating treatment with CS+GH versus celecoxib in 606 patients with Kellgren and Lawrence grades 2–3 knee osteoarthritis and moderate-to-severe pain (Western Ontario and McMaster osteoarthritis index (WOMAC) score ≥301; 0–500 scale). Patients were randomised to receive 400 mg CS plus 500 mg GH three times a day or 200 mg celecoxib every day for 6 months. The primary outcome was the mean decrease in WOMAC pain from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness, visual analogue scale for pain, presence of joint swelling/effusion, rescue medication consumption, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria and EuroQoL-5D.
Results
The adjusted mean change (95% CI) in WOMAC pain was −185.7 (−200.3 to −171.1) (50.1% decrease) with CS+GH and −186.8 (−201.7 to −171.9) (50.2% decrease) with celecoxib, meeting the non-inferiority margin of −40: −1.11 (−22.0 to 19.8; p=0.92). All sensitivity analyses were consistent with that result. At 6 months, 79.7% of patients in the combination group and 79.2% in the celecoxib group fulfilled OMERACT-OARSI criteria. Both groups elicited a reduction >50% in the presence of joint swelling; a similar reduction was seen for effusion. No differences were observed for the other secondary outcomes. Adverse events were low and similarly distributed between groups.
Conclusions
CS+GH has comparable efficacy to celecoxib in reducing pain, stiffness, functional limitation and joint swelling/effusion after 6 months in patients with painful knee osteoarthritis, with a good safety profile.
Trial registration number:
NCT01425853.
doi:10.1136/annrheumdis-2014-206792
PMCID: PMC4717399  PMID: 25589511
Analgesics; NSAIDs; Osteoarthritis
16.  Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies 
Objective
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.
Methods
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.
Results
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Conclusion
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
doi:10.1002/art.38300
PMCID: PMC4660891  PMID: 24757145
20.  The reliability of a novel magnetic resonance imaging-based tool for the evaluation of forefoot bursae in patients with rheumatoid arthritis: the FFB score 
Rheumatology (Oxford, England)  2014;53(11):2014-2017.
Objective. The aim of this study was to determine the reliability of an MRI-based score that evaluates forefoot bursae (FFBs) in patients with RA.
Methods. Items for inclusion, grading criteria and MRI sequences were determined iteratively. The score was evaluated in 30 patients with established RA. Reader agreement was evaluated using the percentage of exact/close agreement, Bland–Altman plots, kappa and intraclass correlation coefficient analyses.
Results. The FFB score assesses nine forefoot regions and contains four items: presence, shape, enhancement and magnetic resonance characteristics. The FFB score showed moderate to good intra- and interreader agreement (κ range = 0.5–0.9 and 0.47–0.87, respectively).
Conclusion. The FFB score is adequately reliable in the evaluation of bursa-like lesions of the forefoot in patients with RA.
doi:10.1093/rheumatology/keu232
PMCID: PMC4202022  PMID: 24907157
magnetic resonance imaging; rheumatoid arthritis; foot; synovium; radiology; outcome measures; disease activity; inflammation; foot
21.  Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study 
Vimaleswaran, Karani S | Cavadino, Alana | Berry, Diane J | Jorde, Rolf | Dieffenbach, Aida Karina | Lu, Chen | Alves, Alexessander Couto | Heerspink, Hiddo J Lambers | Tikkanen, Emmi | Eriksson, Joel | Wong, Andrew | Mangino, Massimo | Jablonski, Kathleen A | Nolte, Ilja M | Houston, Denise K | Ahluwalia, Tarunveer Singh | van der Most, Peter J | Pasko, Dorota | Zgaga, Lina | Thiering, Elisabeth | Vitart, Veronique | Fraser, Ross M | Huffman, Jennifer E | de Boer, Rudolf A | Schöttker, Ben | Saum, Kai-Uwe | McCarthy, Mark I | Dupuis, Josée | Herzig, Karl-Heinz | Sebert, Sylvain | Pouta, Anneli | Laitinen, Jaana | Kleber, Marcus E | Navis, Gerjan | Lorentzon, Mattias | Jameson, Karen | Arden, Nigel | Cooper, Jackie A | Acharya, Jayshree | Hardy, Rebecca | Raitakari, Olli | Ripatti, Samuli | Billings, Liana K | Lahti, Jari | Osmond, Clive | Penninx, Brenda W | Rejnmark, Lars | Lohman, Kurt K | Paternoster, Lavinia | Stolk, Ronald P | Hernandez, Dena G | Byberg, Liisa | Hagström, Emil | Melhus, Håkan | Ingelsson, Erik | Mellström, Dan | Ljunggren, Östen | Tzoulaki, Ioanna | McLachlan, Stela | Theodoratou, Evropi | Tiesler, Carla M T | Jula, Antti | Navarro, Pau | Wright, Alan F | Polasek, Ozren | Hayward, Caroline | Wilson, James F | Rudan, Igor | Salomaa, Veikko | Heinrich, Joachim | Campbell, Harry | Price, Jacqueline F | Karlsson, Magnus | Lind, Lars | Michaëlsson, Karl | Bandinelli, Stefania | Frayling, Timothy M | Hartman, Catharina A | Sørensen, Thorkild I A | Kritchevsky, Stephen B | Langdahl, Bente Lomholt | Eriksson, Johan G | Florez, Jose C | Spector, Tim D | Lehtimäki, Terho | Kuh, Diana | Humphries, Steve E | Cooper, Cyrus | Ohlsson, Claes | März, Winfried | de Borst, Martin H | Kumari, Meena | Kivimaki, Mika | Wang, Thomas J | Power, Chris | Brenner, Hermann | Grimnes, Guri | van der Harst, Pim | Snieder, Harold | Hingorani, Aroon D | Pilz, Stefan | Whittaker, John C | Järvelin, Marjo-Riitta | Hyppönen, Elina
Summary
Background
Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
Methods
In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.
Findings
In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97−0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96−0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002).
Interpretation
Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
doi:10.1016/S2213-8587(14)70113-5
PMCID: PMC4582411  PMID: 24974252
22.  Behavioural physical activity interventions in participants with lower-limb osteoarthritis: a systematic review with meta-analysis 
BMJ Open  2015;5(8):e007642.
Objective
To assess effectiveness of osteoarthritis interventions to promote long-term physical activity behaviour change.
Design
A systematic review and meta-analysis. Protocol registration PROSPERO CRD4201300444 5 (http://www.crd.york.ac.uk/prospero/).
Study selection
Randomised controlled trials (RCTs) comparing physical activity interventions with placebo, no/or minimal intervention in community-dwelling adults with symptomatic knee or hip osteoarthritis. Primary outcomes were change in physical activity or cardiopulmonary fitness after a minimum follow-up of 6 months.
Data extraction
Outcomes were measures of physical activity (self-reported and objectively measured) and cardiovascular fitness. Standard mean differences between postintervention values were used to describe the effect sizes.
Results
27 984 titles were screened and 180 papers reviewed in full. Eleven RCTs satisfied inclusion criteria, total study population of 2741 participants, mean age 62.2. The commonest reasons for study exclusion were follow-up less than 6 months and no physical activity measures. The majority of included interventions implement an arthritis self-management programme targeting coping skills and self-efficacy. Seven studies used self-report measures, the pooled effect of these studies was small with significant heterogeneity between studies (SMD 0.22 with 95% CI −0.11 to 0.56, z=1.30 (p=0.19) I2 statistic of 85%). Subgroup analysis of 6–12 month outcome reduced heterogeneity and increased intervention effect compared to control (SMD 0.53, 95% CI 0.41 to 0.65, z=8.84 (p<0.00001) I2 of 66%).
Conclusions
Arthritis self-management programmes achieve a small but significant improvement in physical activity in the short term. Effectiveness of intervention declines with extended follow-up beyond 12 months with no significant benefit compared to control. The small number of studies (11 RCTs) limited ability to define effective delivery methods. Investigation of behavioural lifestyle interventions for lower limb osteoarthritis populations would benefit from consensus on methodology and outcome reporting. This includes use of validated physical activity reporting tools and planning for long-term follow-up.
doi:10.1136/bmjopen-2015-007642
PMCID: PMC4538274  PMID: 26260348
RHEUMATOLOGY; SPORTS MEDICINE; REHABILITATION MEDICINE
23.  Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Biomarkers and Frailty 
Drugs & Aging  2015;32(7):525-535.
Osteoarthritis (OA), a disease affecting different patient phenotypes, appears as an optimal candidate for personalized healthcare. The aim of the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group was to explore the value of markers of different sources in defining different phenotypes of patients with OA. The ESCEO organized a series of meetings to explore the possibility of identifying patients who would most benefit from treatment for OA, on the basis of recent data and expert opinion. In the first meeting, patient phenotypes were identified according to the number of affected joints, biomechanical factors, and the presence of lesions in the subchondral bone. In the second meeting, summarized in the present article, the working group explored other markers involved in OA. Profiles of patients may be defined according to their level of pain, functional limitation, and presence of coexistent chronic conditions including frailty status. A considerable amount of data suggests that magnetic resonance imaging may also assist in delineating different phenotypes of patients with OA. Among multiple biochemical biomarkers identified, none is sufficiently validated and recognized to identify patients who should be treated. Considerable efforts are also being made to identify genetic and epigenetic factors involved in OA, but results are still limited. The many potential biomarkers that could be used as potential stratifiers are promising, but more research is needed to characterize and qualify the existing biomarkers and to identify new candidates.
doi:10.1007/s40266-015-0276-7
PMCID: PMC4516900  PMID: 26085027
24.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
25.  Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial 
Trials  2015;16:77.
Background
Osteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain.
Methods/Design
Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.
Discussion
The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA.
Trial registration
Current Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).
doi:10.1186/s13063-015-0602-8
PMCID: PMC4351849  PMID: 25872649
Double-blind; Knee osteoarthritis; Methotrexate; Placebo-controlled; Randomized

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