Imperial College London

DrFionaWatt

Faculty of MedicineDepartment of Immunology and Inflammation

Reader in Rheumatology
 
 
 
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f.watt

 
 
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Commonwealth BuildingHammersmith Campus

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Publications

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65 results found

Turnball J, Jha RR, Barrett DA, Valdes AM, Alderson J, Williams A, Vincent TL, Watt F, Chapman Vet al., 2023, The effect of acute knee injury and related knee surgery in young active adults on serum levels of pro- and anti-inflammatory lipid mediators and their associations with knee symptoms, American Journal of Sports Medicine, ISSN: 0363-5465

Background: Despite acute knee injury being a major risk factor for osteoarthritis (OA), the factors that initiate and maintain this risk for longer-term knee symptoms are poorly understood. Bioactive lipids derived from omega-3 and -6 polyunsaturated fatty acids have key roles in the regulation of the inflammatory response, and have been linked to joint damage and osteoarthritis pain in translational models. Hypothesis/Purpose: We hypothesised that there would be associations between systemic levels of bioactive lipids and knee symptoms longitudinally following acute knee injury and related knee surgery.Study Design: This study analysed a subset of serum samples collected at three timepoints after injury from a prospective cohort study of young, active, healthy adults who had sustained acute knee injury (recruited via a surgical care pathway), and in age- and sex-matched controls. Surgery, where it occurred, was performed after the baseline sample was taken and prior to 3 month and 2 year visits.Methods: An LC-MS/MS assay of 41 bioactive lipids was carried out in sera of i) 47 individuals (median age 28; sampled at baseline (median 24 days post-injury), at 3 months and 2 years) with paired Knee Injury and Osteoarthritis Outcome Scores (KOOS)-4, and ii)age- and sex-matched controls.Results: Levels of omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA; p=<0.0001) and docosahexaenoic acid (DHA; p=<0.0001) and the pro-resolution intermediaries 17-, and 14-hydroxydocosahexaenoic acid (HDHA) were all significantly greater at baseline compared with later times, and were also higher than levels in healthycontrols (p=0.0019, & p=<0.0001, respectively). Pro-inflammatory prostaglandins (E2 and D2), leukotriene B4, and thromboxane B2 were significantly lower at the time of injury compared to later times. Higher levels of 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid (DHET) were cross-sectionally associated with more severe knee pain/symp

Journal article

Hollis B, Chatzigeorgiou C, Southam L, Hatzikotoulas K, Kluzek S, Williams A, Zeggini E, Jostins-Dean L, Watt FEet al., 2023, Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank, Osteoarthritis and Cartilage, Vol: 31, Pages: 1377-1387, ISSN: 1063-4584

ObjectiveAcute knee injury is associated with post-traumatic OA (PTOA). Very little is known about the genome-wide associations of PTOA when compared with idiopathic OA (iOA). Our objective was to describe the development of knee OA after knee injury and its genetic associations in UK Biobank (UKB).DesignClinically significant structural knee injuries in those <=50 years were identified from electronic health record and self-reported data in 502,409 UKB participants. Time-to-first knee OA code was compared in injured cases and age-/sex-matched non-injured controls using Cox Proportional Hazards models. A time-to-OA genome-wide association study (GWAS) sought evidence for PTOA risk variants 6 months-20 years following injury. Evidence for associations of two iOA polygenic risk scores (PRS) was sought.ResultsOf 4233 knee injury cases, 1896 (44.8%) were female (mean age at injury 34.1 years [SD10.4]). Over a median of 30.2 (IQR19.5-45.4) years, 1096 (25.9%) of injured cases developed knee OA. The overall hazards ratio (HR) for knee OA after injury was 1.81[1.70,1.93],P=8.9x10-74. Female sex and increasing age at injury were associated with knee OA following injury (HR1.15[1.02,1.30];1.07[1,07,1.07] respectively). OA risk was highest in the first 5 years after injury (HR3.26[2.67,3.98]), persisting for 40 years. In 3074 knee injury cases included in the time-to-OA GWAS, no variants reached genome-wide significance. iOA PRS was not associated with time-to-OA (HR 0.43[0.02,8.41]).ConclusionsIncreasing age at injury and female sex appear to be associated with future development of PTOA in UKB, the risk of which was greatest in the 5 years after injury. Further international efforts towards a better-powered meta-analysis will definitively elucidate genetic similarities and differences of PTOA and iOA.

Journal article

Watt FE, 2023, Is it Autumn for colchicine and osteoarthritis?, The Lancet Rheumatology, Vol: 5, Pages: e240-e241, ISSN: 2665-9913

Journal article

Gulati M, Dursun E, Vincent K, Watt Fet al., 2023, The influence of sex hormones on musculoskeletal pain and osteoarthritis, The Lancet Rheumatology, Vol: 5, Pages: e225-e238, ISSN: 2665-9913

The association of female sex with certain rheumatic symptoms and diseases is now indisputable. Some of the most striking examples of this association occur in individuals with musculoskeletal pain and osteoarthritis, in whom sex-dependent changes in incidence and prevalence of disease are seen throughout the lifecourse. Joint and muscle pain are some of the most common symptoms of menopause, and there is increasingly compelling evidence that changes in or loss of sex hormones (be it natural, autoimmune, pharmacological, or surgical) influence musculoskeletal pain propensity and perhaps disease. However, the effects of modulation or replacement of sex hormones in this context are far less established, particularly whether these approaches could represent a preventative or therapeutic opportunity once symptoms have developed. In this Review, we present evidence for the association of changes in sex hormones with musculoskeletal pain and painful osteoarthritis, discussing data from diverse natural, therapeutic, and experimental settings in humans and relevant animal models relating to hormone loss or replacement and the consequent effects on health, pain, and disease. We also postulate mechanisms by which sex hormones could mediate these effects. Further research is needed; however, increased scientific understanding of this complex area could lead to real benefits in musculoskeletal and women's health.

Journal article

Chester-Jones M, Williams JA, Francis A, Brewer G, Marian IR, Mackworth-Young C, Glover V, Lamb SE, Vincent T, Vincent K, Dutton SJ, Watt FEet al., 2023, Is treating post-menopausal women with symptomatic hand osteoarthritis with hormone replacement therapy feasible?: results from the Hope-E Randomised, Placebo-controlled Feasibility study, World Congress of Osteoarthritis Research Society International (OARSI), Publisher: Elsevier, Pages: S230-S231, ISSN: 1063-4584

Conference paper

Hulme CH, Williams A, Vincent TL, Watt FE, Wright KTet al., 2023, Commonality between the proteome signatures of clinical response to surgically sustained and acute traumatic cartilage injuries in two human knee cohorts, World Congress of Osteoarthritis Research Society International (OARSI), Publisher: Elsevier, Pages: S357-S357, ISSN: 1063-4584

Conference paper

Hollis B, Southam L, Chatzigeorgiou C, Hatzikotoulas K, Kluzek WS, Williams A, Zeggini E, Jostins-Dean L, Watt FEet al., 2023, LIFETIME RISK AND GENETIC PREDISPOSITION TO POST-TRAUMATIC OSTEOARTHRITIS OF THE KNEE: TIME-TO-EVENT AND RELATED ANALYSES IN THE UK BIOBANK, World Congress of Osteoarthritis Research Society International (OARSI), Publisher: ELSEVIER SCI LTD, Pages: S63-S64, ISSN: 1063-4584

Conference paper

Perry TA, Deng Y, Hulley P, Maciewicz RA, Mitchelmore J, Perry D, Larsson S, Lemire S, Struglics A, Appleton CT, Kluzek S, Arden NK, Felson DT, Marsden B, Tom BD, Bondi L, Kapoor M, Kumar V, Lohmander LS, Welting TJ, Walsh DA, Valdes AM, Jostins-Dean L, Watt FE, Vincent TLet al., 2023, SUPPORTIVE EVIDENCE FOR THE POTENTIAL FOR NOVEL BIODISCOVERY IN OSTEOARTHRITIS THROUGH THE STEPUP OA CONSORTIUM, World Congress of Osteoarthritis Research Society International (OARSI), Publisher: ELSEVIER SCI LTD, Pages: S353-S354, ISSN: 1063-4584

Conference paper

Williams JA, Chester-Jones M, Francis A, Brewer G, Gulati M, Lowe CM, Barker K, Julier P, Barber V, Vincent K, Dutton SJ, Watt FEet al., 2023, HOW SHOULD WE BEST MEASURE PARTICIPANT-REPORTED `AVERAGE HAND PAIN': COMPARISON OF TWO METHODS FROM A RANDOMIZED PLACEBO-CONTROLLED FEASIBILITY STUDY OF POST-MENOPAUSAL WOMEN WITH HAND OSTEOARTHRITIS, World Congress of Osteoarthritis Research Society International (OARSI), Publisher: ELSEVIER SCI LTD, Pages: S187-S188, ISSN: 1063-4584

Conference paper

Watt F, Georgopoulos V, 2023, Harmonising knee pain patient-reported outcomes: a systematic literature review and meta-analysis of Patient Acceptable Symptom State (PASS) and individual participant data (IPD), Osteoarthritis and Cartilage, Vol: 31, Pages: 83-95, ISSN: 1063-4584

Objective: In order to facilitate data pooling between studies, we exploredharmonisation of patient-reported outcome measures (PROMS) in people with kneepain due to osteoarthritis or knee trauma, using the Patient Acceptable Symptom Statescores (PASS) as a criterion.Methods: We undertook a systematic literature review (SLR) of PASS scores, andperformed individual participant data (IPD) analysis of score distributions fromconcurrently completed PROM pairs. Numerical rating scales (NRS), visual analoguescales, KOOS and WOMAC pain questionnaires were standardised to 0 to 100 (worst)scales. Meta-regression explored associations of PASS. Bland Altman plots comparedPROM scores within individuals using IPD from WebEx, KICK, MenTOR and NEKOstudies.Results: SLR identified 18 studies reporting PASS in people with knee pain. Pooledstandardised PASS was 27 (95%CI: 21 to 35; n=6339). PASS was statistically similarfor each standardised PROM. Lower PASS was associated with lower baseline pain(β=0.49, p=0.01) and longer time from treatment initiation (Q=6.35, p=0.04). PASSscores were lowest in ligament rupture (12, 95%CI: 11 to 13), but similar between kneeosteoarthritis (31, 95%CI: 26 to 36) and meniscal tear (27, 95%CI: 20 to 35). In IPD,standardised PROMs each revealed similar group mean scores, but scores withinindividuals diverged between PROMs (LoA between -7 to -38 and +25 to 52).Conclusion: Different standardised PROMs give similar PASS thresholds in groupdata. PASS thresholds may be affected more by patient and treatment characteristicsthan between PROMs. However, different PROMs give divergent scores withinindividuals, possibly reflecting different experiences of pain.

Journal article

Jansen MP, Salzlechner C, Barnes E, DiFranco MD, Custers RJH, Watt FE, Vincent TL, Mastbergen SCet al., 2022, Artificial intelligence in osteoarthritis: repair by knee joint distraction shows association of pain, radiographic and immunological outcomes, Rheumatology, Vol: 62, Pages: 2789-2796, ISSN: 1462-0324

ObjectivesKnee joint distraction (KJD) has been associated with clinical and structural improvement and SF marker changes. The current objective was to analyse radiographic changes after KJD using an automatic artificial intelligence-based measurement method and relate these to clinical outcome and SF markers.MethodsTwenty knee osteoarthritis patients were treated with KJD in regular care. Radiographs and WOMAC were collected before and ∼1 year post-treatment. SF was aspirated before, during and after treatment; biomarker levels were assessed by immunoassay. Radiographs were analysed to obtain compartmental minimum and standardized joint space width (JSW), Kellgren–Lawrence (KL) grades, compartmental joint space narrowing (JSN) scores, and osteophytosis and sclerosis scores. Results were analysed for the most affected compartment (MAC) and least affected compartment. Radiographic changes were analysed using the Wilcoxon signed rank test for categorical and paired t-test for continuous variables. Linear regression was used to calculate associations between changes in JSW, WOMAC pain and SF markers.ResultsSixteen patients could be evaluated. JSW, KL and JSN improved in around half of the patients, significant only for MAC JSW (P < 0.05). MAC JSW change was positively associated with WOMAC pain change (P < 0.04). Greater monocyte chemoattractant protein 1 (MCP-1) and lower TGFβ-1 increases were significantly associated with changes in MAC JSW (P < 0.05). MCP-1 changes were positively associated with WOMAC pain changes (P < 0.05).ConclusionAutomatic radiographic measurements show improved joint structure in most patients after KJD in regular care. MAC JSW increased significantly and was associated with SF biomarker level changes and even with improvements in pain as experienced by these patients.

Journal article

Zhu L, Kamalathevan P, Koneva LA, Zarebska JM, Chanalaris A, Ismail H, Wiberg A, Ng M, Muhammad H, Walsby-Tickle J, McCullagh JSO, Watt FE, The Oxford Hand Surgical Team TOHST, Sansom SN, Furniss D, Gardiner MD, Vincent TLet al., 2022, Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis, Science Translational Medicine, Vol: 14, Pages: 1-14, ISSN: 1946-6234

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

Journal article

Williams JAE, Chester-Jones M, Lowe CM, Goff M, Francis A, Brewer G, Marian I, Morris SL, Warwick D, Eldridge L, Julier P, Gulati M, Barker KL, Barber VS, Black J, Woollacott S, Mackworth-Young C, Glover V, Lamb SE, Vincent TL, Vincent K, Dutton SJ, Watt FEet al., 2022, Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study, The Lancet Rheumatology, Vol: 4, Pages: E725-E737, ISSN: 2665-9913

BackgroundSymptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis.MethodsThe HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40–65 years, for whom 1–10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12–15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200.FindingsFrom May 9, 20

Journal article

Paskins Z, Farmer CE, Manning F, Andersson DA, Barlow T, Bishop FL, Brown CA, Clark A, Clark EM, Dulake D, Gulati M, Le Maitre CL, Jones RK, Loughlin J, Mason DJ, McCarron M, Millar NL, Pandit H, Peat G, Richardson SM, Salt EJ, Taylor EJ, Troeberg L, Wilcox RK, Wise E, Wilkinson C, Watt FEet al., 2022, Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method, The Lancet Rheumatology, Vol: 4, Pages: e635-e645, ISSN: 2665-9913

Involving research users in setting priorities for research is essential to ensure the outcomes are patient-centred and maximise its value and impact. The Musculoskeletal Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across musculoskeletal disorders. The Child Health and Nutrition Research Initiative (CHNRI) method of setting research priorities with a range of stakeholders was used, involving four stages and two surveys, to: (1) gather research uncertainties, (2) consolidate these, (3) score uncertainties against importance and impact, and (4) analyse scoring for prioritisation. 213 people responded to the first survey and 285 people to the second, representing clinicians, researchers, and people with musculoskeletal disorders. Key priorities included developing and testing new treatments, better treatment targeting, early diagnosis, prevention, and better understanding and management of pain, with an emphasis on understanding underpinning mechanisms. We present a call to action to researchers and funders to target these priorities.

Journal article

Williams JAE, Chester-Jones M, Francis A, Marian I, Goff M, Brewer G, Gulati M, Eldridge L, Julier P, Minns Lowe C, Barber V, Glover V, Mackworth-Young C, Vincent T, Lamb SE, Vincent K, Dutton SJ, Watt FEet al., 2022, AB0980 Hand Osteoarthritis: investigating Pain Effects in a randomised placebo-controlled feasibility study of estrogen-containing therapy (HOPE-e): report on the primary feasibility outcomes, Annals of the Rheumatic Diseases, Vol: 81, Pages: 1616.2-1617, ISSN: 0003-4967

Background There is an unmet need for new treatments for hand osteoarthritis (OA). Symptomatic hand OA is more common in women and its incidence increases round the age of menopause. Pre-clinical, epidemiological and post hoc studies in Hormone Replacement Therapy (HRT) trials implicate estrogen deficiency as of likely importance in OA aetiopathogenesis. No clinical trials of HRT have been carried out in hand OA to date. The licensed HRT Duavive (conjugated estrogens + SERM bazedoxifene) was selected on its potential for efficacy and tolerability.Objectives We set out to determine the feasibility and acceptability of this form of HRT in post-menopausal women with hand OA, to generate proof of concept data and refine methods for a full study.Methods ISRCTN12196200. Females aged 40-65 yrs and 1-10yrs after final menstrual period with hand OA fulfilling ACR criteria and 2+ painful hand joints were recruited. Eligibility incorporated best practice for HRT prescription but did not require menopausal symptoms. Recruitment was at 3 sites in primary/secondary care, including directly from the community. Design was parallel group, double-blind 1:1 randomisation of Duavive or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before stopping. Routes and rates of recruitment and the acceptability of randomisation, medication (compliance, retention), and proposed outcomes were measured, and the likelihood of unblinding. Measures related to hand pain and function, menopause symptoms and joint appearance. Patient and Public Involvement actively informed study rationale, design and materials. An end of study questionnaire and 2 participant focus groups provided further acceptability data.Results Recruitment was for 12/possible 18 months, interrupted due to COVID-19. Some study procedures were modified to allow reopening whilst collecting all primary outcomes. 434 enquiries/referrals were received, leading to 96 telephone pre-screens, of which 33 gave written informe

Journal article

Georgopoulos V, Perry TA, Smith SL, McWilliams DF, Gohir S, Valdes AM, Steultjens M, Woodburn J, Vincent TL, Watt FE, Walsh DAet al., 2022, CAN CONTINUOUS KNEE PAIN OUTCOME MEASURES BE HARMONISED?, Publisher: ELSEVIER SCI LTD, Pages: S15-S17, ISSN: 1063-4584

Conference paper

Vincent TL, Watt FE, 2022, Osteoarthritis, Medicine, Vol: 50, Pages: 116-124, 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 the 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 previously led to significant academic apathy in this disease area, reflected not only in our poor understanding of disease pathogenesis, but also in the failure to classify the disease with greater precision and develop sensitive tools for diagnosis and prognostic assessment. The identification of key degradative enzymes in cartilage, the appreciation that damaged articular cartilage has repair capabilities and the recognition that ‘good’ and ‘bad’ mechanical stress triggers different molecular pathways have greatly changed the 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. The disease remains the most common reason for joint replacement surgery. There are no licensed disease-modifying OA drugs but recent clinical trials suggest that these may be within reach.

Journal article

Zhu L, Kamalathevan P, Koneva L, Zarebska JM, Chanalaris A, Ismail H, Wiberg A, Ng M, Muhammed H, Watt FE, Sansom S, Furniss D, Gardiner MD, Vincent TLet al., 2021, Variants in<i>ALDH1A2</i>reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis

<jats:title>Abstract</jats:title><jats:p>Over 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease modifying treatments for this disabling condition. Common polymorphic variants in<jats:italic>ALDH1A2</jats:italic>, that encodes the key enzyme in the synthesis of all-trans retinoic acid (atRA), have been associated with severe hand OA. In this study, we sought to elucidate the biological significance of this association. We first confirmed that<jats:italic>ALDH1A2</jats:italic>risk variants were associated with hand OA in UK Biobank. Articular cartilage was acquired from 33 consenting individuals with hand OA at the time of routine hand OA surgery. They were stratified by genotype and RNA sequencing performed. A reciprocal relationship between<jats:italic>ALDH1A2</jats:italic>mRNA and inflammatory genes was observed. Articular cartilage injury up-regulates similar inflammatory genes by a process that we have previously termed mechanoflammation, and which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-dependent genes, indicative of cellular atRA levels, and both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator activated receptor (PPAR)-γ dependent mechanism. Talarozole, delivered by minipump, was able to suppress mechano-inflammatory genes in articular cartilage<jats:italic>in vivo</jats:italic>6h after mouse knee joint destabilization, and reduced cartilage degradation and osteophyte formation after 4 weeks. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>, and identifies RAMBAs as potential dise

Working paper

Garriga C, Goff M, Paterson E, Hrusecka R, Hamid B, Alderson J, Leyland K, Honeyfield L, Greenshields L, Satchithananda K, Lim A, Arden NK, Judge A, Williams A, Vincent TL, Watt FEet al., 2021, Clinical and molecular associations with outcomes at two years after acute knee injury: a longitudinal study in the Knee Injury Cohort at the Kennedy (KICK), The Lancet Rheumatology, Vol: 3, Pages: e648-e658, ISSN: 2665-9913

Background: Joint Injury is a major risk factor for osteoarthritis (OA) and an opportunity to prospectively examine its early processes. We investigated whether predefined baseline factors including demographic, clinical factors and protein analytes in knee synovial fluid (sf/SF) and in plasma/serum were associated with clinically relevant outcomes at two years after knee injury.Methods: This was a longitudinal cohort study (REC10/H0805/39;NCT02667756) with 150 individuals aged 16-50 recruited within 8 weeks of a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically being treated surgically. Twelve SF and four plasma/serum biomarkers were measured by immunoassay as the exposures of interest. Primary outcome was “Knee Injury and Osteoarthritis Outcome Score” (KOOS)4. X-ray/3T-MRI knees were taken at baseline and two years. Linear and logistic regression models adjusting for predefined covariates assessed associations with 2year KOOS4 and secondary endpoints including new symptomatic (regular knee symptoms), tibio-femoral radiographic OA (TFROA, Kellgren Lawrence Grade 2 or more on an X-ray) respectively. Findings: Baseline KOOS4, medium/large knee effusion and moderate/severe SF blood staining and their interaction significantly predicted 2year KOOS4 (Coeff. -20·5 [95% confidence interval -34·8, -6·18]. Of the predefined markers, only sfMCP-1 and sfIL-6 -showed independent associations with 2year KOOS4 (-0.015[0.027,-0.004] and -0.0005[-0.0009,-0.0001] per change in 1 pg/ml units respectively), jointly with the interaction of effusion and blood staining accounting for 39% of outcome variability. New TFROA at two years was associated with baseline meniscal tear (OR5·7[1·25,25·92]). 13/22(59·1%) with new TFROA had no NHANES frequent knee symptoms. Only 3month medium/large effusion was associated with new symptomatic TFROA at two years (OR14·0[1·86

Journal article

Watt FE, Wise EM, 2021, Osteoarthritis and associated comorbidities: new answers and more questions, Rheumatology, Vol: 60, Pages: 3966-3968, ISSN: 1462-0324

Journal article

Jansen MP, Mastbergen SC, Watt FE, Willemse EJ, Vincent TL, Spruijt S, Emans PJ, Custers RJH, van Heerwaarden RJ, Lafeber FPJGet al., 2021, Cartilage Repair Activity during Joint-Preserving Treatment May Be Accompanied by Osteophyte Formation, APPLIED SCIENCES-BASEL, Vol: 11

Journal article

Sofat N, Watt FE, Lyn Tan A, 2021, Development of medical therapeutics in osteoarthritis: time for action to improve patient care, Rheumatology, Vol: 60, Pages: 3487-3489, ISSN: 1462-0324

Journal article

Marian IR, Goff M, Williams JAE, Gulati M, Chester-Jones M, Francis A, Watson M, Vincent TL, Woollacott S, Mackworth-Young C, Glover V, Furniss D, Gardiner M, Lamb SE, Vincent K, Barber VS, Black J, Dutton SJ, Watt FEet al., 2021, Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial, Pilot and Feasibility Studies, Vol: 7, Pages: 1-14, ISSN: 2055-5784

BackgroundHand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design.MethodsThis is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60–90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study.DiscussionIdentifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable informati

Journal article

Watt FE, Gulati M, Brewer G, Judge A, Kennedy D, Vincent TLet al., 2021, The relationship of hand osteoarthritis symptom onset with menopause and menopausal hormonal therapy-results of a retrospective secondary care study, The Virtual 2021 OARSI World Congress on Osteoarthritis, Publisher: Elsevier, Pages: S283-S283, ISSN: 1063-4584

Purpose: Hand osteoarthritis (OA) is more common in women and previous studies have noted its incidence increases around the time of the menopause. More recently, there has been a report in a large primary care dataset of increased incidence of hand OA following cessation of menopausal hormonal therapy (MHT). We set out to describe the temporal relationship between menopause, use of MHT and the onset of hand symptoms in a population of women with hand OA in a secondary care (rheumatology) setting. Our objectives were: i) to explore if there was a temporal relationship between the onset of menopause and the onset of hand OA symptoms; ii) to describe if current or previous use of MHT was associated with the timing of onset of hand OA symptoms; iii) To examine if cessation of MHT was associated with onset of hand OA symptoms.Methods: This was a retrospective review of UK NHS medical records (UK IRAS ethics #282499). Sequential females aged 18 years and older referred to specialist hand OA clinic in London, UK 2007-2015 with a diagnosis of Hand OA by accepted clinical criteria were included; exclusions were other forms of arthritis or causes of hand pain. Predefined outcome measures were reported age of onset of hand symptoms, reported age of Final Menstrual Period (FMP); predefined variables were use of systemic estrogen-containing MHT (subgroups current, previous, never users) and menopausal status (premenopausal, post-menopausal [at least one year post FMP]; peri-menopausal period defined as FMP+/- 4 years). These variables, age and other demographics were from the usual healthcare records, with all predefined variables recorded by standardised proforma used routinely in this setting. Descriptive statistics and linear regression modelling (coefficient, 95% CI are given) were carried out in STATA IC.Results: 82/98 females were post-menopausal, with mean age at FMP of 50. In these post-menopausal women, median time from FMP to hand symptom onset was 3 years (range -25

Conference paper

Mason D, Englund M, Watt FE, 2021, Prevention of posttraumatic osteoarthritis at the time of injury: Where are we now, and where are we going?, Journal of Orthopaedic Research, Vol: 39, Pages: 1152-1163, ISSN: 0736-0266

This overview of progress made in preventing post-traumatic osteoarthritis (PTOA) was delivered in a workshop at the Orthopaedics Research Society Annual Conference in 2019. As joint trauma is a major risk factor for OA, defining the molecular changes within the joint at the time of injury may enable the targeting of biological processes to prevent later disease. Animal models have been used to test therapeutic targets to prevent PTOA. A review of drug treatments for PTOA in rodents and rabbits between 2016 and 2018 revealed 11 systemic interventions, 5 repeated intra-articular or topical interventions, and 5 short-term intra-articular interventions, which reduced total Osteoarthritis Research Society International scores by 30%–50%, 20%–70%, and 0%–40%, respectively. Standardized study design, reporting of effect size, and quality metrics, alongside a “whole joint” approach to assessing efficacy, would improve the translation of promising new drugs. A roadblock to translating preclinical discoveries has been the lack of guidelines on the design and conduct of human trials to prevent PTOA. An international workshop addressing this in 2016 considered inclusion criteria and study design, and advocated the use of experimental medicine studies to triage candidate treatments and the development of early biological and imaging biomarkers. Human trials for the prevention of PTOA have tested anakinra after anterior cruciate ligament rupture and dexamethasone after radiocarpal injury. PTOA offers a unique opportunity for defining early mechanisms of OA to target therapeutically. Progress in trial design and high-quality preclinical research, and allegiance with patients, regulatory bodies, and the pharmaceutical industry, will advance this field.

Journal article

Watt FE, 2021, Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis?, Current Opinion in Rheumatology, Vol: 33, Pages: 74-83, ISSN: 1040-8711

PURPOSE OF REVIEW: Current thinking in the study of posttraumatic osteoarthritis (PTOA) is overviewed: the osteoarthritis which follows acute joint injury. The review particularly highlights important publications in the last 18 months, also reflecting on key older literature, in terms of what have we have we learned and have yet to learn from PTOA, which can advance the osteoarthritis field as a whole. RECENT FINDINGS: PTOA is a mechanically driven disease, giving insight into mechanical drivers for osteoarthritis. A mechanosensitive molecular tissue injury response (which includes activation of pain, degradative and also repair pathways) is triggered by acute joint injury and seen in osteoarthritis. Imaging features of PTOA are highly similar to osteoarthritis, arguing against it being a different phenotype. The inflammatory pathways activated by injury contribute to early joint symptoms. However, later structural changes appear to be dissociated from traditional measures of synovial inflammation. SUMMARY: PTOA remains an important niche in which to understand processes underlying osteoarthritis and seek interventional targets. Whether PTOA has true molecular or clinical differences to osteoarthritis as a whole remains to be understood. This knowledge is important for a field where animal modelling of the disease relies heavily on the link between injury and osteoarthritis.

Journal article

Paskins Z, Manning F, Farmer C, Le Maitre C, Clark E, Mason D, Wilkinson C, Andersson D, Barlow T, Bishop F, Brown C, Clark A, Dulake D, Gulati M, Jones R, Loughlin J, McCarron M, Millar N, Pandit H, Peat G, Richardson S, Salt E, Taylor-Wormald J, Troeberg L, Wilcox R, Wise E, Rudkin S, Watt FEet al., 2021, Versus Arthritis Musculoskeletal Disorders Research Advisory Group Priority Setting Exercise Protocol

Involving research users in setting priorities for musculoskeletal research is essential to raise awareness of the unmet needs for MSK research, to ensure research outcomes are patient-centred and relevant, have a high likelihood of resulting in patient benefit, reduce research waste and increase research value and impact. In 2018, Versus Arthritis convened an MSK Disorders Research Advisory Group (RAG) which included people with arthritis, health care professionals and researchers in MSK, in order to identify and prioritise research areas with a long-term aim of improving quality and impact of MSK research. On further review, there were few previous prioritisation approaches in this area looking across discovery science to more clinical research, at important research questions which might be common to a range of disorders or approaches incorporating input at all stages of the process by a range of stakeholders including people with arthritis. The group identified that more work to define research priorities in these areas was justified and designed a research priority setting process for MSK disorders. This manuscript documents the methodology that was developed by the group for this process. <h4>Methods</h4> Following a review, the Child Health and Nutrition Research Initiative (CHNRI) method for research prioritisation was selected as best aligning with the needs of this process. The group agreed on adaptations to the CHNRI approach, context, purpose and remit of the exercise and identified through consensus four priority research Domains: Mechanisms of disease; Diagnosis (including early diagnosis) and measuring the impact of these disorders; Living well with MSK disorders and Successful Translation. From all published CHNRI scoring criteria for generated research avenues or themes of research, the group identified six which were most relevant to this process. To ensure accessibility of the survey and scoring, these were refined to three: Equity (co

Journal article

Stucker S, Chen J, Watt FE, Kusumbe APet al., 2020, Bone angiogenesis and vascular niche remodeling in stress, aging, and diseases, Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X

The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.

Journal article

Mennan C, Hopkins T, Channon A, Elliott M, Johnstone B, Kadir T, Loughlin J, Peffers M, Pitsillides A, Sofat N, Stewart C, Watt FE, Zeggini E, Holt C, Roberts S, OATech Network Consortiumet 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.

Journal article

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