51 results found
Watt F, Georgopoulos V, 2022, 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, 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.
Watt F, 2022, Treating post-menopausal women with symptomatic hand osteoarthritis with hormone replacement therapy (conjugated estrogens and bazedoxifene): primary report from the HOPE-e randomised placebo-controlled feasibility study, The Lancet Rheumatology, ISSN: 2665-9913
Background: Symptomatic hand osteoarthritis (OA) is more common in women and its incidence increases round the age of menopause, implicating estrogen deficiency. No randomised clinical trials (RCTs) of hormone replacement therapy (HRT) have been carried out in hand OA. We set out to determine the feasibility and acceptability of a RCT of a form of HRT (conjugated estrogens-bazedoxifene) in post-menopausal women with painful hand OA.Methods: ISRCTN12196200. Females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and ≥2 painful hand joints were recruited across three primary/secondary care sites and the community. Design was parallel group, double-blind 1:1 randomisation of conjugated estrogens-bazedoxifene or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before study end. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Secondary outcomes generated proof-of-concept quantitative and qualitative data, assessing acceptability of proposed outcomes for a full trial (hand pain/function/appearance, menopause symptoms), and adverse events (AEs), to refine study design. Analysis was intention-to-treat. Progression criteria were pre-defined.Findings: From May2019-Dec2020, 434 enquiries/referrals were received. 33 individuals gave written informed consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed. Of 96 telephone pre-screens, 28/35 (80%(95%CI 63%,92%)) eligible participants were randomised. All 28 participants completed all follow-ups with high compliance and outcome measure completeness. All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs were reported. Participants/investigators were well blinded (participant index 0·50(95%CI 0·25,0·75)). Interpretation: This first ever feasibility study
Paskins Z, Farmer CE, Manning F, et 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.
Williams JAE, Chester-Jones M, Francis A, et 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
Paskins Z, Farmer CE, Manning F, et al., 2022, Research priorities to reduce the impact of Musculoskeletal Disorders: a priority setting exercise using the CHNRI method, The Lancet Rheumatology, ISSN: 2665-9913
Involving research users in setting priorities for research is essential to ensure research outcomes are patient-centred and to maximise research value and impact. The Musculoskeletal (MSK) Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across MSK disorders. The Child Health and Nutrition Research Initiative (CHRNI) method of setting research priorities with a range of stakeholders was utilised, 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 and 285 people responded to the first and second surveys respectively, representing clinicians, researchers and people with MSK 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.
Georgopoulos V, Perry TA, Smith SL, et al., 2022, CAN CONTINUOUS KNEE PAIN OUTCOME MEASURES BE HARMONISED?, Publisher: ELSEVIER SCI LTD, Pages: S15-S17, ISSN: 1063-4584
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.
Garriga C, Goff M, Paterson E, et 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
Watt FE, Wise EM, 2021, Osteoarthritis and associated comorbidities: new answers and more questions, Rheumatology, Vol: 60, Pages: 3966-3968, ISSN: 1462-0324
Jansen MP, Mastbergen SC, Watt FE, et al., 2021, Cartilage repair activity during joint-preserving treatment may be accompanied by osteophyte formation, Applied Sciences (Switzerland), Vol: 11
Knee joint distraction (KJD) treatment has shown cartilage repair and clinical improvement in patients with osteoarthritis, as has high tibial osteotomy (HTO). Following KJD, TGFβ-1 and IL-6 were increased in synovial fluid (SF), factors related to cartilage regeneration, but also to osteophyte formation. As such, osteophyte formation after both joint-preserving treatments was studied. Radiographic osteophyte size was measured before, one year, and two years after treatment. Changes were compared with natural progression in patients from the CHECK cohort before un-dergoing total knee arthroplasty. An additional KJD cohort underwent SF aspiration, and one-year Altman osteophyte score changes were compared to SF-marker changes during treatment. After two years, both KJD (n = 58) and HTO (n = 38) patients showed an increase in osteophyte size (+6.2 mm2 and +7.0 mm2 resp.; both p < 0.004), with no significant differences between treatments (p = 0.592). Untreated CHECK patients (n = 44) did not show significant two-year changes (+2.1 mm2; p = 0.207) and showed significant differences with KJD and HTO (both p < 0.044). In SF aspiration patients (n = 17), there were significant differences in TGFβ-1 changes (p = 0.044), but not IL-6 (p = 0.898), between patients with a decrease, no change, or increase in osteophyte Altman score. Since KJD and HTO showed joint space widening and clinical improvement accompanied by osteophyte formation, increased osteophytosis after joint-preserving treatments may be a bystander effect of cartilage repair activity related to intra-articular factors like TGFβ-1 and raises questions regarding osteophyte formation as solely characteristic of the joint degenerative process.
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
Marian IR, Goff M, Williams JAE, et 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
Watt FE, Gulati M, Brewer G, et 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
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.
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.
Stucker S, Chen J, Watt FE, et 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.
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
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 Cartilage, Vol: 28, Pages: 324-333
OBJECTIVE: Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. METHOD: 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS4) was collected at baseline, 3, 6 and 12 months. RESULTS: 13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ≥2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFβ-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS4 over 6 months showed greater increases in FGF-2 and TGFβ-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS4 over 12 months. CONCLUSION: Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.
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., J Proteome Res, Vol: 18, Pages: 4231-4239
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.
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 Cartilage, Vol: 27, Pages: 1590-1598
OBJECTIVE: To investigate the TrkA inhibitor, ASP7962, for treatment of painful knee osteoarthritis. DESIGN: Phase 2a, double-blind, placebo- and naproxen-controlled, double-dummy, parallel-group study. Adults with knee osteoarthritis were randomized (2:2:1) to ASP7962 (100 mg), placebo, or naproxen (500 mg) twice daily (BID) for 4 weeks. Primary endpoint: change from baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale score. Secondary endpoints: change from baseline to Weeks 1, 2, and End of Treatment (EoT) in WOMAC pain subscale score; change from baseline to Weeks 1, 2, 4, and EoT in WOMAC physical function and stiffness subscales, walking pain and WOMAC total scores; and change from baseline in daily average pain score. RESULTS: 215 participants were randomized (ASP7962 100 mg BID, n = 85; placebo, n = 87; naproxen 500 mg BID, n = 43). No significant difference was observed between ASP7962 and placebo in change from baseline to Week 4 in WOMAC pain subscale score (-0.14; 90% 2-sided CI: -0.62, 0.34; P = 0.316); a significant difference was observed between naproxen and placebo (-0.67; 80% 2-sided CI: -1.12, -0.23; P = 0.027). No differences were observed between ASP7962 and placebo in change from baseline in any WOMAC subscale score; statistically significant changes were observed between naproxen and placebo (P ≤ 0.01, all time points for all WOMAC endpoints). ASP7962 was safe and well-tolerated. CONCLUSIONS: Four-week treatment with ASP7962 (100 mg BID) did not improve pain or physical function in individuals with painful knee osteoarthritis. ClinicalTrials.gov, NCT02611466; EudraCT Number, 2014-004996-22.
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., Nat Rev Rheumatol, Vol: 14, Pages: 641-656
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.
Kingsbury SR, Tharmanathan P, Keding A, et al., 2018, Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial., Ann Intern Med, Vol: 168, Pages: 385-395
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: Hydroxychloro
Kingsbury SR, Tharmanathan P, Keding A, et al., 2018, Hydroxychloroquine to reduce symptoms of hand osteoarthritis, Annals of Internal Medicine, Vol: 168, 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, 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.
Watt FE, 2018, Osteoarthritis biomarkers: year in review., Osteoarthritis Cartilage, Vol: 26, Pages: 312-318
OBJECTIVE: To summarise important findings from biomarker studies relevant to osteoarthritis (OA), published between April 2016 and March 2017; to consider these findings in the context of new discoveries and technologies, and clinical and scientific need in OA. DESIGN: Studies were selected by PubMed search, conducted between 01/04/2016 and 01/03/2017. MeSH terms [biomarker] AND [OA] were used; the search was restricted to Human, English language and Full Text Available publications, which yielded 50 eligible publications. Any biomarker was considered, including non-proteins and other clinical measurements. RESULTS: Three main areas are overviewed: 1) Studies examining highly validated biomarkers, in the FNIH OA Biomarkers Consortium and elsewhere, particularly their ongoing application and validation. Control reference intervals, work on predictive validity and other longitudinal studies examining prognostic value of biomarkers in large cohorts are reviewed. 2) Novel studies relating to biomarkers of inflammation are discussed, including complement, the performance of markers of so-called 'cold inflammation' and results from clinical trials including biomarkers. 3) Discovery studies, including whole blood RNA, proteomics and metabolomics are reviewed, with an emphasis on new technologies. CONCLUSIONS: Discovery, characterisation and qualification of various biomarkers is ongoing; several novel protein and non-protein candidate biomarkers have been reported this year. Biomarkers provide us with an opportunity to better diagnose and stratify the disease, via established panels or new discovery approaches. Improving quality of sampling and testing, and measuring large numbers of markers simultaneously in large cohorts would seem likely to identify new clinically applicable biomarkers, which are still much needed in this disease.
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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