Publications
67 results found
Mennan C, Hopkins T, Channon A, et al., 2020, The use of technology in the subcategorisation of osteoarthritis: a Delphi study approach., Osteoarthritis and Cartilage Open, Vol: 2, Pages: 1-8, ISSN: 2665-9131
OBJECTIVE: This UK-wide OATech Network + consensus study utilised a Delphi approach to discern levels of awareness across an expert panel regarding the role of existing and novel technologies in osteoarthritis research. To direct future cross-disciplinary research it aimed to identify which could be adopted to subcategorise patients with osteoarthritis (OA). DESIGN: An online questionnaire was formulated based on technologies which might aid OA research and subcategorisation. During a two-day face-to-face meeting concordance of expert opinion was established with surveys (23 questions) before, during and at the end of the meeting (Rounds 1, 2 and 3, respectively). Experts spoke on current evidence for imaging, genomics, epigenomics, proteomics, metabolomics, biomarkers, activity monitoring, clinical engineering and machine learning relating to subcategorisation. For each round of voting, ≥80% votes led to consensus and ≤20% to exclusion of a statement. RESULTS: Panel members were unanimous that a combination of novel technological advances have potential to improve OA diagnostics and treatment through subcategorisation, agreeing in Rounds 1 and 2 that epigenetics, genetics, MRI, proteomics, wet biomarkers and machine learning could aid subcategorisation. Expert presentations changed participants' opinions on the value of metabolomics, activity monitoring and clinical engineering, all reaching consensus in Round 2. X-rays lost consensus between Rounds 1 and 2; clinical X-rays reached consensus in Round 3. CONCLUSION: Consensus identified that 9 of the 11 technologies should be targeted towards OA subcategorisation to address existing OA research technology and knowledge gaps. These novel, rapidly evolving technologies are recommended as a focus for emergent, cross-disciplinary osteoarthritis research programmes.
Garriga C, Goff M, Leyland K, et al., 2020, PREDICTIVE FACTORS FOR PATIENT REPORTED SYMPTOMS AND RADIOGRAPHIC STRUCTURAL CHANGE AT 2 YEARS AFTER ACUTE KNEE INJURY, OARSI World Congress on Osteoarthritis - Promoting Clinical and Basic Research in Osteoarthritis, Publisher: ELSEVIER SCI LTD, Pages: S322-S323, ISSN: 1063-4584
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- Citations: 2
Watt FE, Hamid B, Garriga C, et al., 2020, The molecular profile of synovial fluid changes upon joint distraction and is associated with clinical response in knee osteoarthritis, OSTEOARTHRITIS AND CARTILAGE, Vol: 28, Pages: 324-333, ISSN: 1063-4584
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- Citations: 32
Watt FE, 2020, New treatments for osteoarthritis must be based on evidence, The Lancet Rheumatology, Vol: 2, Pages: e6-e8, ISSN: 2665-9913
Ruiz-Romero C, Lam MPY, Nilsson P, et al., 2019, Mining the Proteome Associated with Rheumatic and Autoimmune Diseases, JOURNAL OF PROTEOME RESEARCH, Vol: 18, Pages: 4231-4239, ISSN: 1535-3893
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- Citations: 10
Watt FE, Blauwet MB, Fakhoury A, et al., 2019, Tropomyosin-related kinase A (TrkA) inhibition for the treatment of painful knee osteoarthritis: results from a randomized controlled phase 2a trial, OSTEOARTHRITIS AND CARTILAGE, Vol: 27, Pages: 1590-1598, ISSN: 1063-4584
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- Citations: 20
Watt FE, Corp N, Kingsbury SR, et al., 2019, Towards prevention of post-traumatic osteoarthritis: report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury, Osteoarthritis and Cartilage, Vol: 27, Pages: 23-33, ISSN: 1063-4584
OBJECTIVE: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. DESIGN: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. RESULTS: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. CONCLUSIONS: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.
Marshall M, Watt FE, Vincent TL, et al., 2018, Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management, NATURE REVIEWS RHEUMATOLOGY, Vol: 14, Pages: 641-656, ISSN: 1759-4790
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- Citations: 90
Kingsbury SR, Tharmanathan P, Keding A, et al., 2018, Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis A Randomized Trial, ANNALS OF INTERNAL MEDICINE, Vol: 168, Pages: 385-+, ISSN: 0003-4819
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- Citations: 45
Kingsbury SR, Tharmanathan P, Keding A, et al., 2018, Hydroxychloroquine to Reduce Symptoms of Hand Osteoarthritis, ANNALS OF INTERNAL MEDICINE, Vol: 168, Pages: I30-I30, ISSN: 0003-4819
Vincent TL, Watt FE, 2018, Osteoarthritis, Medicine (United Kingdom), Vol: 46, Pages: 187-195, ISSN: 1357-3039
Osteoarthritis (OA) is the most common form of joint disease, and its impact is set to grow as the prevalence of obesity rises and our elderly population increases. Many clinicians regard OA as simply a disease of ‘wear and tear’ and by implication one in which disease modification is not possible. Such prejudices have led to significant academic apathy in this disease, reflected not only in our poor understanding of disease pathogenesis, but also in the failure to classify the disease with greater precision, and to develop sensitive tools for diagnosis and prognostic assessment. The identification of key degradative enzymes in cartilage and the use of mouse models to study disease pathogenesis have greatly changed our outlook in recent years. Evidence-based management of the condition is outlined in international guidelines: education, weight control/loss and exercise (general, joint-specific) are core interventions. Analgesia and non-pharmacological and surgical approaches that favourably affect joint biomechanics are used for treating painful OA unresponsive to core interventions; there are no disease-modifying OA drugs. Ultimately, this disease remains the most common reason for total joint replacement. The next decade is likely to see significant advances in our understanding, and treatment, of this condition.
Watt FE, 2018, Osteoarthritis biomarkers: year in review, OSTEOARTHRITIS AND CARTILAGE, Vol: 26, Pages: 312-318, ISSN: 1063-4584
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- Citations: 54
Watt FE, 2018, Musculoskeletal pain and menopause., Post Reprod Health, Vol: 24, Pages: 34-43
Musculoskeletal pain, arthralgia and arthritis are all more common in women, and their frequency increases with age and in some appears to be associated with the onset of menopause. The clinical assessment, investigation and management of women presenting with musculoskeletal pain, arthralgia or arthritis at the time of menopause are reviewed. Common causes of arthralgia and arthritis in this population are discussed. The epidemiological and trials evidence for the effects of hormone replacement therapy on musculoskeletal pain and arthritis (primarily from RCTs of HRT for other menopausal symptoms) are discussed. Lastly, the possible underlying aetiological roles of sex hormones including estrogen, and their deficiency, in predisposing to musculoskeletal pain and arthritis are overviewed. Although the association appears strong, a causal link between estrogen deficiency and musculoskeletal pain or different types of arthritis is lacking; there have been few studies specifically within this group of symptomatic patients, and there is much still to understand about musculoskeletal pain and arthritis at the time of the menopause, and about how we might prevent or treat this.
Coathup V, Finlay T, Teare HJA, et al., 2018, Making the most of the waiting room: Electronic patient engagement, a mixed methods study, DIGITAL HEALTH, Vol: 4, ISSN: 2055-2076
Kingsbury SR, Tharmanathan P, Keding A, et al., 2017, Hydroxychloroquine in hand OA; results of the UK HERO trial (vol 25, pg S3, 2017), OSTEOARTHRITIS AND CARTILAGE, Vol: 25, Pages: 2147-2147, ISSN: 1063-4584
Kingsbury SR, Tharmanathan P, Keding A, et al., 2017, HYDROXYCHLOROQUINE IN HAND OA; RESULTS OF THE UK HERO TRIAL, World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis, Publisher: ELSEVIER SCI LTD, Pages: S3-S4, ISSN: 1063-4584
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- Citations: 3
Watt FE, Gulati M, 2017, New drug treatments for osteoarthritis: what is on the horizon?, European Medical Journal Rheumatology, Vol: 2, Pages: 50-58, ISSN: 2056-6395
Osteoarthritis (OA) is the most common form of arthritis, yet has historically lagged far behind rheumatoid arthritis in terms of drug development. Despite the many challenges presented by clinical trials in OA, improvements in our understanding of disease pathogenesis and a move to treat pain, as well as underlying disease process, mean there are now many new pharmacological therapies currently in various stages of clinical trials. The medical need for these therapies and the evidence for recent tissue and molecular targets are reviewed. Current therapeutic examples in each area are discussed, including both novel therapeutics and existing agents which may be repurposed from other disease areas. Some challenges remain, but opportunities for improving symptoms and disease process in OA in the clinic with new pharmacological agents would appear to be on the close horizon.
Watt FE, Paterson E, Freidin A, et al., 2016, Acute molecular changes in synovial fluid following human knee injury: association with early clinical outcomes, Arthritis & Rheumatology, Vol: 68, Pages: 2129-2140, ISSN: 2326-5205
ObjectiveTo investigate whether molecules found to be up-regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient-reported outcomes in the 3 months after injury.MethodsSeven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme-linked immunosorbent assay.ResultsSix of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG-6). There was low-to-moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1, or TSG-6 had lower KOOS4). These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL-6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months.ConclusionOur findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient-reported outcomes over this early period, with SF IL-6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease ris
Kingsbury SR, Corp N, Watt FE, et al., 2016, Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group, Rheumatology, Vol: 55, Pages: 1394-1402, ISSN: 1462-0324
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.
Felson DT, Redmond AC, Chapman GJ, et al., 2016, Recommendations for the conduct of efficacy trials of treatment devices for osteoarthritis: a report from a working group of the Arthritis Research UK Osteoarthritis and Crystal Diseases Clinical Studies Group, RHEUMATOLOGY, Vol: 55, Pages: 320-326, ISSN: 1462-0324
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- Citations: 14
Watt FE, 2016, Hand osteoarthritis, menopause and menopausal hormone therapy, MATURITAS, Vol: 83, Pages: 13-18, ISSN: 0378-5122
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- Citations: 34
Nazareth R, Cashman P, Parlier P, et al., 2015, Semi-automation of knee cartilage thickness estimation in Magnetic Resonance Images with metal artefact, Osteoarthritis Research Society International
Kingsbury SR, Tharmanathan P, Arden NK, et al., 2015, 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, Vol: 16, Pages: 1-14, ISSN: 1745-6215
BackgroundOsteoarthritis (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/DesignPain 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-trea
Watt FE, Kennedy DL, Carlisle KE, et al., 2014, Night-time immobilization of the distal interphalangeal joint reduces pain and extension deformity in hand osteoarthritis, Rheumatology, Vol: 53, Pages: 1142-1149, ISSN: 1462-0332
Objective. DIP joint OA is common but has few cost-effective, evidence-based interventions. Pain anddeformity [radial or ulnar deviation of the joint or loss of full extension (extension lag)] frequently lead tofunctional and cosmetic issues. We investigated whether splinting the DIP joint would improve pain,function and deformity.Methods. A prospective, radiologist-blinded, non-randomized, internally controlled trial of custom splintingof the DIP joint was carried out. Twenty-six subjects with painful, deforming DIP joint hand OA gavewritten, informed consent. One intervention joint and one control joint were nominated. A custom guttersplint was worn nightly for 3 months on the intervention joint, with clinical and radiological assessment atbaseline, 3 and 6 months. Differences in the change were compared by the Wilcoxon signed rank test.Results. The median average pain at baseline was similar in the intervention (6/10) and control joints(5/10). Average pain (primary outcome measure) and worst pain in the intervention joint were significantlylower at 3 months compared with baseline (P = 0.002, P = 0.02). Differences between intervention andcontrol joint average pain reached significance at 6 months (P = 0.049). Extension lag deformity was significantlyimproved in intervention joints at 3 months and in splinted joints compared with matchedcontralateral joints (P = 0.016).Conclusion. Short-term night-time DIP joint splinting is a safe, simple treatment modality that reduces DIPjoint pain and improves extension of the digit, and does not appear to give rise to non-compliance,increased stiffness or joint restriction.
Chong K-W, Chanalaris A, Burleigh A, et al., 2013, Fibroblast growth factor 2 drives changes in gene expression following injury to murine cartilage in vitro and In Vivo, Arthritis and Rheumatism, Vol: 65, Pages: 2346-2355, ISSN: 0004-3591
ObjectiveThe articular cartilage is known to be highly mechanosensitive, and a number of mechanosensing mechanisms have been proposed as mediators of the cellular responses to altered mechanical load. These pathways are likely to be important in tissue homeostasis as well as in the pathogenesis of osteoarthritis. One important injury-activated pathway involves the release of pericellular fibroblast growth factor 2 (FGF-2) from the articular cartilage. Using a novel model of murine cartilage injury and surgically destabilized joints in mice, we examined the extent to which FGF-2 contributes to the cellular gene response to injury.MethodsFemoral epiphyses from 5-week-old wild-type mice were avulsed and cultured in serum-free medium. Explant lysates were Western blotted for phospho-JNK, phospho-p38, and phospho-ERK or were fixed for immunohistochemical analysis of the nuclear translocation of p65 (indicative of NF-κB activation). RNA was extracted from injured explants, rested explants that had been stimulated with recombinant FGF-2 or FGF-18, or whole joints from either wild-type mice or FGF-2−/− mice. Reverse transcription–polymerase chain reaction was performed to examine a number of inflammatory response genes that had previously been identified in a microarray analysis.ResultsMurine cartilage avulsion injury resulted in rapid activation of the 3 MAP kinase pathways as well as NF-κB. Almost all genes identified in murine joints following surgical destabilization were also regulated in cartilage explants upon injury. Many of these genes, including those for activin A (Inhba), tumor necrosis factor–stimulated gene 6 (Tnfaip6), matrix metalloproteinase 19 (Mmp19), tissue inhibitor of metalloproteinases 1 (Timp1), and podoplanin (Pdpn), were significantly FGF-2 dependent following injury to cartilage in vitro and to joint tissues in vivo.ConclusionFGF-2–dependent gene expression occurs in vitro and in vivo in response to cartil
Strollo R, Ponchel F, Malmstrom V, et al., 2013, Autoantibodies to Posttranslationally Modified Type II Collagen as Potential Biomarkers for Rheumatoid Arthritis, ARTHRITIS AND RHEUMATISM, Vol: 65, Pages: 1702-1712, ISSN: 0004-3591
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- Citations: 47
Watt FE, Kennedy D, Carlisle K, et al., 2013, NIGHT-TIME SPLINTING OF THE DISTAL INTERPHALANGEAL JOINT REDUCES PAIN AND IMPROVES EXTENSION AT THE JOINT: RESULTS FROM THE SPLINT-OA STUDY, World Congress of the Osteoarthritis-Research-Society-International (OARSI), Publisher: ELSEVIER SCI LTD, Pages: S25-S26, ISSN: 1063-4584
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- Citations: 1
Kingsbury SR, Tharmanathan P, Adamson J, et al., 2013, Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial, Trials, Vol: 14, Pages: 1-12, ISSN: 1745-6215
BackgroundOsteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain.Methods/designHERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. 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.DiscussionThe HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a n
Watt FE, Ismail HM, Didangelos A, et al., 2013, Src and Fibroblast Growth Factor 2 Independently Regulate Signaling and Gene Expression Induced by Experimental Injury to Intact Articular Cartilage, ARTHRITIS AND RHEUMATISM, Vol: 65, Pages: 397-407, ISSN: 0004-3591
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- Citations: 30
Alexander S, Watt F, Sawaji Y, et al., 2007, Activin a is an anticatabolic autocrine cytokine in articular cartilage whose production is controlled by fibroblast growth factor 2 and NF-κB, ARTHRITIS AND RHEUMATISM, Vol: 56, Pages: 3715-3725, ISSN: 0004-3591
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- Citations: 22
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