Publications by authors named "Fiona E Watt"

21 Publications

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Clinical and molecular associations with outcomes at 2 years after acute knee injury: a longitudinal study in the Knee Injury Cohort at the Kennedy (KICK).

Lancet Rheumatol 2021 Sep 24;3(9):e648-e658. Epub 2021 Jun 24.

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.

Background: Joint injury is a major risk factor for osteoarthritis and provides an opportunity to prospectively examine early processes associated with osteoarthritis. We investigated whether predefined baseline demographic and clinical factors, and protein analytes in knee synovial fluid and in plasma or serum, were associated with clinically relevant outcomes at 2 years after knee injury.

Methods: This longitudinal cohort study recruited individuals aged 16-50 years between Nov 1, 2010, and Nov 28, 2014, across six hospitals and clinics in London, UK. Participants were recruited within 8 weeks of having a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically treated surgically. We measured several predefined clinical variables at baseline (eg, time from injury to sampling, extent and type of joint injury, synovial fluid blood staining, presence of effusion, self-reported sex, age, and BMI), and measured 12 synovial fluid and four plasma or serum biomarkers by immunoassay at baseline and 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 years, adjusted for baseline score, assessed in all patients. Linear and logistic regression models adjusting for predefined covariates were used to assess associations between baseline variables and 2-year KOOS. This study is registered with ClinicalTrials.gov, number NCT02667756.

Findings: We enrolled 150 patients at a median of 17 days (range 1-59, IQR 9-26) after knee injury. 123 (82%) were male, with a median age of 25 years (range 16-50, IQR 21-30). 98 (65%) of 150 participants completed a KOOS at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable adjusted analysis. In the 2-year dataset mean KOOS improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS (n=77; coefficient -20·5, 95% CI -34·8 to -6·18; p=0·0060). The only predefined biomarkers that showed independent associations with 2-year KOOS were synovial fluid MCP-1 (n=77; -0·015, 0·027 to -0·004 per change in 1 pg/mL units; p=0·011) and IL-6 (n=77; -0·0005, -0·0009 to -0·0001 per change in 1 pg/mL units; p=0·017). These biomarkers, combined with the interaction of effusion and blood staining, accounted for 39% of outcome variability. Two adverse events occurred that were linked to study participation, both at the time of blood sampling (one presyncopal episode, one tenderness and pain at the site of venepuncture).

Interpretation: The combination of effusion and haemarthrosis was significantly associated with symptomatic outcomes after acute knee injury. The synovial fluid molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic outcomes but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process need to be better understood to make clinical progress.

Funding: Versus Arthritis, Kennedy Trust for Rheumatology Research, and NIHR Oxford Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2665-9913(21)00116-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390381PMC
September 2021

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial.

Pilot Feasibility Stud 2021 Jun 24;7(1):133. Epub 2021 Jun 24.

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.

Background: Hand 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.

Methods: This 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.

Discussion: Identifying 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 information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference.

Trial Registration: ISRCTN12196200 registered on 15 January 2019.
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http://dx.doi.org/10.1186/s40814-021-00869-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223359PMC
June 2021

Osteoarthritis and associated comorbidities: new answers and more questions.

Rheumatology (Oxford) 2021 09;60(9):3966-3968

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences (NDORMS), Oxford, University of Oxford, Oxford.

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http://dx.doi.org/10.1093/rheumatology/keab405DOI Listing
September 2021

Development of medical therapeutics in osteoarthritis: time for action to improve patient care.

Rheumatology (Oxford) 2021 08;60(8):3487-3489

NIHR Leeds Biomedical Research Centre, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

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http://dx.doi.org/10.1093/rheumatology/keab263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328507PMC
August 2021

Prevention of posttraumatic osteoarthritis at the time of injury: Where are we now, and where are we going?

J Orthop Res 2021 06 4;39(6):1152-1163. Epub 2021 Mar 4.

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1002/jor.24982DOI Listing
June 2021

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases.

Front Cell Dev Biol 2020 26;8:602269. Epub 2020 Nov 26.

Tissue and Tumor Microenvironments Group, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom.

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.
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http://dx.doi.org/10.3389/fcell.2020.602269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726257PMC
November 2020

Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis?

Authors:
Fiona E Watt

Curr Opin Rheumatol 2021 01;33(1):74-83

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1097/BOR.0000000000000760DOI Listing
January 2021

Mining the Proteome Associated with Rheumatic and Autoimmune Diseases.

J Proteome Res 2019 12 23;18(12):4231-4239. Epub 2019 Oct 23.

Grupo de Investigación de Reumatología, INIBIC-Complejo Hospitalario Universitario de A Coruña, SERGAS , Departamento de Medicina Universidad de A Coruña , A Coruña 15006 , Spain.

A steady increase in the incidence of osteoarthritis and other rheumatic diseases has been observed in recent decades, including autoimmune conditions such as rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. Rheumatic and autoimmune diseases (RADs) are characterized by the inflammation of joints, muscles, or other connective tissues. In addition to often experiencing debilitating mobility and pain, RAD patients are also at a higher risk of suffering comorbidities such as cardiovascular or infectious events. Given the socioeconomic impact of RADs, broad research efforts have been dedicated to these diseases worldwide. In the present work, we applied literature mining platforms to identify "popular" proteins closely related to RADs. The platform is based on publicly available literature. The results not only will enable the systematic prioritization of candidates to perform targeted proteomics studies but also may lead to a greater insight into the key pathogenic processes of these disorders.
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http://dx.doi.org/10.1021/acs.jproteome.9b00360DOI Listing
December 2019

Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management.

Nat Rev Rheumatol 2018 11;14(11):641-656

Research Institute for Primary Care and Health Sciences, Arthritis Research UK Primary Care Centre, David Weatherall Building, Keele University, Keele, UK.

Osteoarthritis (OA) is a highly prevalent condition, and the hand is the most commonly affected site. Patients with hand OA frequently report symptoms of pain, functional limitations and frustration in undertaking everyday activities. The condition presents clinically with changes to the bone, ligaments, cartilage and synovial tissue, which can be observed using radiography, ultrasonography or MRI. Hand OA is a heterogeneous disorder and is considered to be multifactorial in aetiology. This Review provides an overview of the epidemiology, presentation and burden of hand OA, including an update on hand OA imaging (including the development of novel techniques), disease mechanisms and management. In particular, areas for which new evidence has substantially changed the way we understand, consider and treat hand OA are highlighted. For example, genetic studies, clinical trials and careful prospective imaging studies from the past 5 years are beginning to provide insights into the pathogenesis of hand OA that might uncover new therapeutic targets in the disease.
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http://dx.doi.org/10.1038/s41584-018-0095-4DOI Listing
November 2018

Making the most of the waiting room: Electronic patient engagement, a mixed methods study.

Digit Health 2018 Jan-Dec;4:2055207617751304. Epub 2018 Jan 10.

4Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.

Objective: The purpose of this study was to explore whether patients with musculoskeletal conditions would agree to use digital technologies to learn about research registries and make a decision about signing up whilst in the clinic waiting room.

Methods: Patients were recruited from four hospital clinics across Oxfordshire. We used an explanatory mixed methods design with two sequential phases comprising an exploratory, cross-sectional questionnaire ( = 84), followed by focus group interviews ( = 8) to provide context for the findings from the questionnaire. Multivariate ordinal logistic regression models were used to explore relationships between patient preferences and characteristics. Thematic analysis was used to understand the reasons for patient preferences regarding digital technologies and research registries.

Results: As participants' age increased, they were more likely to report a preference for face-to-face recruitment methods compared to those using digital technologies. Findings from the focus groups indicated this was primarily due to a fear of technology and physical limitations associated with a patient's condition. Patients also reported a preference for making a decision about signing up at a later date, which was attributed to patients feeling distracted whilst in the waiting room due to anxieties related to their upcoming appointment.

Conclusions: Many patients with musculoskeletal conditions in the UK may be interested in learning about opportunities to participate in research whilst using digital technologies within the waiting room. The results suggest the need for choice regarding the presentation and format of information and whether it can be accessed at a later date at home.
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http://dx.doi.org/10.1177/2055207617751304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001187PMC
January 2018

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial.

Ann Intern Med 2018 03 20;168(6):385-395. Epub 2018 Feb 20.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds, United Kingdom (S.R.K., A.G., R.J.W., P.G.C.).

Background: Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse.

Objective: To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis.

Design: Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104).

Setting: 13 primary and secondary care centers in England.

Participants: Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point.

Intervention: Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care.

Measurements: The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done.

Results: At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of -0.16 point (95% CI, -0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group).

Limitation: Hydroxychloroquine dosage restrictions may have reduced efficacy.

Conclusion: Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.

Primary Funding Source: Arthritis Research UK.
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http://dx.doi.org/10.7326/M17-1430DOI Listing
March 2018

Musculoskeletal pain and menopause.

Authors:
Fiona E Watt

Post Reprod Health 2018 Mar 7;24(1):34-43. Epub 2018 Feb 7.

Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1177/2053369118757537DOI Listing
March 2018

New Drug Treatments for Osteoarthritis: What is on the Horizon?

Eur Med J Rheumatol 2017 Mar;2(1):50-58

Department of Rheumatology, Royal Free Hospital, London, UK.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198938PMC
March 2017

Harmonising data collection from osteoarthritis studies to enable stratification: recommendations on core data collection from an Arthritis Research UK clinical studies group.

Rheumatology (Oxford) 2016 08 15;55(8):1394-402. Epub 2016 Apr 15.

Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, University of Oxford MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

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.
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http://dx.doi.org/10.1093/rheumatology/kew201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957675PMC
August 2016

Acute Molecular Changes in Synovial Fluid Following Human Knee Injury: Association With Early Clinical Outcomes.

Arthritis Rheumatol 2016 09;68(9):2129-40

Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Objective: To 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.

Methods: Seven 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.

Results: Six 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.

Conclusion: Our 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 risk.
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http://dx.doi.org/10.1002/art.39677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006850PMC
September 2016

Hand osteoarthritis, menopause and menopausal hormone therapy.

Authors:
Fiona E Watt

Maturitas 2016 Jan 1;83:13-8. Epub 2015 Oct 1.

Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom. Electronic address:

Hand osteoarthritis (OA) is one of the commonest musculoskeletal conditions, primarily affecting women over the age of 50, typically around the age of the menopause. Symptomatic disease can give rise to substantial pain, impairment of hand function and quality of life, leading to significant socioeconomic cost. There is currently no disease-modifying therapy, representing a huge unmet clinical need. The evidence for a relationship between hand OA and the menopause is summarised. Whether there is evidence for an effect of menopausal hormonal therapy on the incidence, prevalence or severity of symptomatic hand OA is critically reviewed, and gaps in our knowledge identified. Lastly, the potential mechanisms by which estrogen, or newer agents such as SERMs, might act to interfere with disease pathogenesis are overviewed. The need for specifically designed, controlled trials of agents in cohorts with symptomatic hand OA, refractory to standard symptomatic management is highlighted.
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http://dx.doi.org/10.1016/j.maturitas.2015.09.007DOI Listing
January 2016

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 Mar 4;16:77. Epub 2015 Mar 4.

Leeds Institute of Rheumatic and Musculoskeletal Medicine and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapeltown Road, Leeds, LS7 4SA, UK.

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).
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http://dx.doi.org/10.1186/s13063-015-0602-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351849PMC
March 2015

Night-time immobilization of the distal interphalangeal joint reduces pain and extension deformity in hand osteoarthritis.

Rheumatology (Oxford) 2014 Jun 8;53(6):1142-9. Epub 2014 Feb 8.

Arthritis Research UK Centre for OA Pathogenesis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, Rheumatology Department, Therapies Department, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Centre for Haematology, Hammersmith Hospital, Imperial College London, Imaging Department, Charing Cross Hospital, Imperial College Healthcare NHS Trust and Department of Imaging, King's College Hospital, London, UK.Arthritis Research UK Centre for OA Pathogenesis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, Rheumatology Department, Therapies Department, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Centre for Haematology, Hammersmith Hospital, Imperial College London, Imaging Department, Charing Cross Hospital, Imperial College Healthcare NHS Trust and Department of Imaging, King's College Hospital, London, UK.

Objective: DIP joint OA is common but has few cost-effective, evidence-based interventions. Pain and deformity [radial or ulnar deviation of the joint or loss of full extension (extension lag)] frequently lead to functional 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 splinting of the DIP joint was carried out. Twenty-six subjects with painful, deforming DIP joint hand OA gave written, informed consent. One intervention joint and one control joint were nominated. A custom gutter splint was worn nightly for 3 months on the intervention joint, with clinical and radiological assessment at baseline, 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 significantly lower at 3 months compared with baseline (P = 0.002, P = 0.02). Differences between intervention and control joint average pain reached significance at 6 months (P = 0.049). Extension lag deformity was significantly improved in intervention joints at 3 months and in splinted joints compared with matched contralateral joints (P = 0.016).

Conclusion: Short-term night-time DIP joint splinting is a safe, simple treatment modality that reduces DIP joint pain and improves extension of the digit, and does not appear to give rise to non-compliance, increased stiffness or joint restriction.

Trial Registration: clinical trials.gov, http://clinicaltrials.gov, NCT01249391.
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http://dx.doi.org/10.1093/rheumatology/ket455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023558PMC
June 2014

Fibroblast growth factor 2 drives changes in gene expression following injury to murine cartilage in vitro and in vivo.

Arthritis Rheum 2013 Sep;65(9):2346-55

Kennedy Institute of Rheumatology and University of Oxford, London, UK.

Objective: The 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.

Methods: Femoral 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.

Results: Murine 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.

Conclusion: FGF-2-dependent gene expression occurs in vitro and in vivo in response to cartilage/joint injury in mice.
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http://dx.doi.org/10.1002/art.38039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992838PMC
September 2013

Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial.

Trials 2013 Mar 2;14:64. Epub 2013 Mar 2.

Division of Rheumatic and Musculoskeletal Disease and National Institute of Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS7 4SA, UK.

Background: Osteoarthritis (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/design: HERO 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.

Discussion: The 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 new treatment for OA, which could be of particular use in the primary care setting.

Trial Registration: ISRCTN91859104.
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http://dx.doi.org/10.1186/1745-6215-14-64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716636PMC
March 2013

Src and fibroblast growth factor 2 independently regulate signaling and gene expression induced by experimental injury to intact articular cartilage.

Arthritis Rheum 2013 Feb;65(2):397-407

Kennedy Institute of Rheumatology, University of Oxford, 65 Aspenlea Road, London W6 8LH, UK.

Objective: To investigate whether cartilage injury activates protein tyrosine kinases distinct from fibroblast growth factor (FGF)-related signaling, and whether they contribute to injury-induced gene responses.

Methods: Phosphokinases and protein tyrosine phosphorylation were assayed by Western blotting of cartilage lysates. Immunoprecipitation and Western blotting with 4G10 antibody and immunoprecipitation kinase assay were carried out. Tyrosine-phosphorylated proteins on silver-stained gels of injured cartilage lysates were identified by mass spectrometry. Messenger RNA induction in cartilage explants was assessed by quantitative reverse transcriptase-polymerase chain reaction.

Results: Protein tyrosine phosphorylation occurred within seconds of injury to the surface of intact articular cartilage, as did activation of MAPKs and IKK. Activation did not reoccur upon reinjury of cultured explants. The prominent tyrosine-phosphorylated proteins focal adhesion kinase, paxillin, and cortactin were identified as substrates of Src family kinases. The Src family kinase inhibitor PP2 blocked injury-induced tyrosine phosphorylation. It did not prevent activation of the MAPKs and IKK but differentially inhibited 8 of 10 inflammatory response genes that were induced by injury. In contrast, FGF signaling blockade with PD173074 reduced all MAPK and IKK activation by ∼50% and inhibited a different subset of genes but had no effect on Src-like signaling.

Conclusion: Injury to the surface of intact articular cartilage activates Src-like kinases as well as MAPKs and IKK (implying NF-κB activation). FGF-2 contributes to MAPK/IKK activation but not to Src-like signaling, suggesting that the latter is a parallel pathway that also regulates the injury-induced inflammatory gene response.
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http://dx.doi.org/10.1002/art.37765DOI Listing
February 2013
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