Recent Submissions

  • The association of painful and non-painful morbidities with frailty: a cross sectional analysis of a cohort of community dwelling older people in England.

    Walsh, David A (BMC Geriatrics, 2024-02)
    Introduction: The association between chronic pain and frailty might indicate that pain is an independent driver of frailty but might alternatively be explained by inclusion within frailty identification tools of morbidities that commonly lead to chronic pain. This research examines the extent to which the association of pain with frailty might be attributed to morbidities. Methods: A cross-sectional analysis of older people in a UK cohort with or at risk of musculoskeletal problems or frailty (Investigating Musculoskeletal Health and Wellbeing study), used multivariable logistic regression and Z-tests to assess the degrees of associations of pain (McGill Pain Rating Index), and painful and non-painful morbidity counts with frailty (modified FRAIL questionnaire). Results: Data were from 2,185 participants, 56% female, median age 73 (range 60 to 96) years. 430 (20%) participants were classified as frail. In a fully adjusted standardised model, pain (aOR 2.07 (95%CI 1.83 to 2.33) and 'any' morbidity aOR (1.74 (95%CI 1.54 to 1.97) were both significantly associated with frailty. When morbidity was subclassified as painful or non-painful, painful (aOR 1.48 (95%CI 1.30 to 1.68) and non-painful (aOR1.39 (95%CI 1.24 to 1.56)) morbidities each were associated with frailty, as also was pain (aOR 2.07 (95%CI 1.83 to 2.34, p < 0.001). Conclusions: Pain is associated with frailty, over and above any effect of painful and non-painful morbidities. This forms the justification for future research which focuses on pain management in the identification, prevention, and treatment of frailty.
  • The STAR care pathway for patients with chronic pain after total knee replacement: four-year follow-up of a randomised controlled trial

    Walsh, David A (BMC Musculoskeletal Disorders, 2023-12)
    Background: The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. Methods: Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0-10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. Results: Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and - 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. Conclusions: The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years.
  • Osteoarthritis pain phenotypes: How best to cut the cake?

    Walsh, David A
    Heterogeneity within clinical populations raises challenges and opportunities for improving treatment. Osteoarthritis (OA) treatments often adhere to the ‘one size fits all’ utilitarian approach, suggesting that everyone will gain the greatest benefit from the same treatment. However, OA is a heterogeneous condition, with multiple pathologies driving different outcomes. No single outcome is necessarily equally important for all people. Increasingly recognized as a disease of the whole joint, OA affects articular cartilage, subchondral bone, and synovium, resulting in a clinical syndrome in which pain is predominant.
  • Associations of Muscle Strength with Central Aspects of Pain: Data from the Knee Pain and Related Health in the Community (KPIC) Cohort.

    Walsh, David A (Journal of Personalized Medicine, 2023-09)
    Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (β = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.
  • Health economic impact of moderate-to-severe chronic pain associated with osteoarthritis in England: a retrospective analysis of linked primary and secondary care data

    Walsh, David A (BMJ Open, 2023-07)
    Objective Despite the prevalence of osteoarthritis (OA) in England, few studies have examined the health economic impact of chronic pain associated with OA. The aim of this study was to compare outcomes in patients with moderate-to-severe chronic pain associated with OA and matched controls without known OA. Design Retrospective, longitudinal, observational cohort study. Setting Electronic records extracted from the Clinical Practice Research Datalink GOLD primary care database linked to Hospital Episode Statistics (HES) data set. Participants Patients (cases; n=5931) ≥18 years and with existing diagnosis of OA and moderate-to-severe pain associated with their OA, and controls matched on age, sex, comorbidity burden, general practitioner (GP) practice and availability of HES data. Interventions None. Primary and secondary outcome measures Total healthcare resource use (HCRU) and direct healthcare costs during 0–6, 0–12, 0–24 and 0–36 months of follow-up. Secondary outcomes measures included pharmacological management and time to total joint replacement. Results Patients with moderate-to-severe chronic pain associated with OA used significantly more healthcare services versus matched controls, reflected by higher HCRU and significantly higher direct costs. During the first 12 months’ follow-up, cases had significantly more GP consultations, outpatient attendances, emergency department visits and inpatient stays than matched controls (all p<0.0001). Total mean costs incurred by cases during 0–12 months’ follow-up were five times higher in cases versus controls (mean (SD): £4199 (£3966) vs £781 (£2073), respectively). Extensive cycling through pharmacological therapies was observed; among cases, 2040 (34.4%), 1340 (22.6%), 841 (14.2%), 459 (7.7%) and 706 (11.9%) received 1–5, 6–10, 11–15, 16–20 and >20 lines of therapy, respectively. Conclusions This wide-ranging, longitudinal, observational study of real-world primary and secondary care data demonstrates the impact of moderate-to-severe chronic pain associated with OA in patients compared with matched controls. Further studies are required to fully quantify the health economic burden of moderate-to-severe pain associated with OA.
  • Association between pain intensity and depressive symptoms in community-dwelling adults: longitudinal findings from the Survey of Health, Ageing and Retirement in Europe (SHARE).

    Walsh, David A
    Purpose: To investigate the longitudinal associations between pain and depressive symptoms in adults. Methods: Prospective cohort study on data from 28,515 community-dwelling adults ≥ 50 years, free from depression at baseline (Wave 5), with follow-up in Wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE). Significant depressive symptoms were defined by a EURO-D score ≥ 4. The longitudinal association between baseline pain intensity and significant depressive symptoms at follow-up was analysed using logistic regression models; odds ratios (ORs) and confidence intervals (CI) were calculated, adjusting for socio-demographic and clinical factors, physical inactivity, loneliness, mobility and functional impairments. Results: Mean age was 65.4 years (standard deviation 9.0, range 50-99); 14,360 (50.4%) participants were women. Mean follow-up was 23.4 (standard deviation 3.4) months. At baseline, 2803 (9.8%) participants reported mild pain, 5253 (18.4%) moderate pain and 1431 (5.0%) severe pain. At follow-up, 3868 (13.6%) participants-1451 (10.3%) men and 2417 (16.8%) women-reported significant depressive symptoms. After adjustment, mild, moderate and severe baseline pain, versus no pain, were associated with an increased likelihood of significant depressive symptoms at follow-up: ORs (95% CI) were 1.20 (1.06-1.35), 1.32 (1.20-1.46) and 1.39 (1.19-1.63), respectively. These associations were more pronounced in men compared to women, and consistent in participants aged 50-64 years, those without mobility or functional impairment, and those without loneliness at baseline. Conclusion: Higher baseline pain intensity was longitudinally associated with a greater risk of significant depressive symptoms at 2-year follow-up, in community-dwelling adults without baseline depression.
  • The bidirectional relationship between chronic joint pain and frailty: data from the Investigating Musculoskeletal Health and Wellbeing cohort.

    Walsh, David A (BMC Geriatrics, 2023-05)
    Background: Pain and frailty are associated, but this relationship is insufficiently understood. We aimed to test whether there is a unidirectional or bidirectional relationship between joint pain and frailty. Methods: Data were from Investigating Musculoskeletal Health and Wellbeing, a UK-based cohort. Average joint pain severity over the previous month was assessed using an 11-point numerical rating scale (NRS). Frailty was classified as present/absent using the FRAIL questionnaire. Multivariable regression assessed the association between joint pain and frailty, adjusted for age, sex, and BMI class. Two-wave cross-lagged path modelling permitted simultaneous exploration of plausible causal pathways between pain intensity and frailty at baseline and 1-year. Transitions were assessed using t-tests. Results: One thousand one hundred seventy-nine participants were studied, 53% female, with a median age of 73 (range 60 to 95) years. FRAIL classified 176 (15%) participants as frail at baseline. Mean (SD) baseline pain score was 5.2 (2.5). Pain NRS ≥ 4 was observed in 172 (99%) of frail participants. Pain severity was associated with frailty at baseline (aOR 1.72 (95%CI 1.56 to 1.92)). In cross-lagged path analysis, higher baseline pain predicted 1-year frailty [β = 0.25, (95%CI 0.14 to 0.36), p < 0.001] and baseline frailty predicted higher 1-year pain [β = 0.06, (95%CI 0.003 to 0.11), p = 0.040]. Participants transitioning to frailty over one year had higher mean pain scores (6.4 (95%CI 5.8 to 7.1)) at baseline than those who remained non-frail (4.7 (95%CI 4.5 to 4.8)), p < 0.001. Conclusions: The bidirectional relationship between pain and frailty could lead to a vicious cycle in which each accelerates the other's progression. This justifies attempts to prevent frailty by addressing pain and to include pain measures as an outcome in frailty studies.
  • Inflammatory and Noninflammatory Disease Activity in Rheumatoid Arthritis: The Effect of Pain on Personalized Medicine.

    Walsh, David A
    Disease activity in rheumatoid arthritis (RA) is often described in terms of inflammation, although noninflammatory mechanisms are also integral to the disease. Pain is the most important symptom for many people with RA,1 and is therefore a key component of clinically relevant measures of RA disease activity.
  • Osteoarthritis Bone Marrow Lesions.

    Walsh, David A (Osteoarthritis and Cartilage, 2023-01)
    Assessment and treatment of Bone Marrow Lesions (BMLs) could ultimately make step changes to the lives of people with osteoarthritis (OA). We here review the imaging and pathological characteristics of OA-BMLs, their differential diagnosis and measurement, and cross-sectional and longitudinal associations with pain and OA structural progression. We discuss how biomechanical and cellular factors may contribute to BML pathogenesis, and how pharmacological and non-pharmacological interventions that target BMLs might reduce pain and OA structural progression. We critically appraise semiquantitative and quantitative methods for assessing BMLs, and their potential utilities for identifying people at risk of symptomatic and structural OA progression, and evaluating treatment responses. New interventions that target OA-BMLs should both confirm their importance, and reduce the unacceptable burden of OA.
  • How people with knee pain understand why their pain changes or remains the same over time: A qualitative study.

    Walsh, David A (Osteoarthritis and Cartilage Open, 2023)
    Objectives Guidelines recommend knee osteoarthritis pain management based on biopsychosocial mechanisms. Treatment adherence and effectiveness may be affected if there is a mismatch between patient perspectives and treatment focus. We therefore examined patient perspectives on mechanisms of their knee pain, why it persisted or changed over the past year, whether their understanding had changed, and whether their understanding aligned with that of others with whom they interact. Methods Individuals with chronic knee pain (n ​= ​50) were purposively recruited from the Knee Pain and related health In the Community (KPIC) cohort to represent worsened, improved, or unchanged pain or anxiety between baseline and one year later. Framework analysis, a comparative form of thematic analysis, was used across transcripts of semi-structured telephone interviews. Results Data were collapsed into themes of diagnosis, joint structure, ageing, physical activity, weight management, and treatment. Participants focused on biomechanical rather than psychological pain mechanisms. Some participants attributed pain improvement to increased and others to decreased physical activity. Participants reported no change in their understanding of their pain during the preceding year, but that their attitudes to pain, for example acceptance, had changed. Participants reported that they and others around them lacked understanding of their pain and why it did or did not change. Conclusion People report a predominantly biomechanical understanding of why their knee pain remains constant or changes over time. Clinicians should support patients to develop a biopsychosocial understanding of knee pain aligned to treatment across the range of biological, psychological, and social modalities.
  • Chronic pain in people living with dementia: challenges to recognising and managing pain, and personalising intervention by phenotype

    Walsh, David A (Age and Ageing, 2023-01)
    Pain is common in people with dementia, and pain can exacerbate the behavioural and psychological symptoms of dementia. Effective pain management is challenging, not least in people with dementia. Impairments of cognition, communication and abstract thought can make communicating pain unreliable or impossible. It is unclear which biopsychosocial interventions for pain management are effective in people with dementia, and which interventions for behavioural and psychological symptoms of dementia are effective in people with pain. The result is that drugs, physical therapies and psychological therapies might be either underused or overused. People with dementia and pain could be helped by assessment processes that characterise an individual's pain experience and dementia behaviours in a mechanistic manner, phenotyping. Chronic pain management has moved from a 'one size fits all' approach, towards personalised medicine, where interventions recommended for an individual depend upon the key mechanisms underlying their pain, and the relative values they place on benefits and adverse effects. Mechanistic phenotyping through careful personalised evaluation would define the mechanisms driving pain and dementia behaviours in an individual, enabling the formulation of a personalised intervention strategy. Central pain processing mechanisms are particularly likely to be important in people with pain and dementia, and interventions to accommodate and address these may be particularly helpful, not only to relieve pain but also the symptoms of dementia.
  • Influence of Social Support, Financial Status, and Lifestyle on the Disparity Between Inflammation and Disability in Rheumatoid Arthritis.

    Walsh, David A
    Objective: To investigate how social support, financial status, and lifestyle influence the development of excess disability in rheumatoid arthritis (RA). Methods: Data were obtained from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort study of people with RA. A previous analysis identified groups with similar inflammation trajectories but markedly different disability over 10 years; those in the higher disability trajectory groups were defined as having "excess disability." Self-reported data regarding contextual factors (social support, financial situation, lifestyle) were obtained from participants, and they completed patient-reported outcome measures (pain, fatigue, anxiety, depression) at baseline. The direct effect of the contextual factors on excess disability and the effect mediated by patient-reported outcome measures were assessed using structural equation models. Findings were validated in 2 independent data sets (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN]). Results: Of 538 included ESPOIR participants (mean age ± SD 48.3 ± 12.2 years; 79.2% women), 200 participants (37.2%) were in the excess disability group. Less social support (β = 0.17 [95% confidence interval (95% CI) 0.08, 0.26]), worse financial situation (β = 0.24 [95% CI 0.14, 0.34]), less exercise (β = 0.17 [95% CI 0.09-0.25]), and less education (β = 0.15 [95% CI 0.06, 0.23]) were associated with excess disability group membership; smoking, alcohol consumption, and body mass index were not. Fatigue and depression mediated a small proportion of these effects. Similar results were seen in NOAR and ERAN. Conclusion: Greater emphasis is needed on the economic and social contexts of individuals with RA at presentation; these factors might influence disability over the following decade.
  • Association of pain and risk of falls in community-dwelling adults: a prospective study in the Survey of Health, Ageing and Retirement in Europe (SHARE).

    Walsh, David A
    Purpose: To investigate the longitudinal associations between pain and falls risks in adults. Methods: Prospective cohort study on data from 40,636 community-dwelling adults ≥ 50 years assessed in Wave 5 and 6 in the Survey of Health, Ageing and Retirement in Europe (SHARE). Socio-demographic and clinical information was collected at baseline (Wave 5). At 2-year follow-up (Wave 6), falls in the previous 6 months were recorded. The longitudinal associations between pain intensity, number of pain sites and pain in specific anatomic sites, respectively, and falls risk were analysed by binary logistic regression models; odds ratios (95% confidence intervals) were calculated. All analyses were adjusted for socio-demographic and clinical factors and stratified by sex. Results: Mean age was 65.8 years (standard deviation 9.3; range 50-103); 22,486 (55.3%) participants were women. At follow-up, 2805 (6.9%) participants reported fall(s) in the previous 6 months. After adjustment, participants with moderate and severe pain at baseline had an increased falls risk at follow-up of 1.35 (1.21-1.51) and 1.52 (1.31-1.75), respectively, compared to those without pain (both p < 0.001); mild pain was not associated with falls risk. Associations between pain intensity and falls risk were greater at younger age (p for interaction < 0.001). Among participants with pain, pain in ≥ 2 sites or all over (multisite pain) was associated with an increased falls risk of 1.29 (1.14-1.45) compared to pain in one site (p < 0.001). Conclusions: Moderate, severe and multisite pain were associated with an increased risk of subsequent falls in adults.
  • THE ASSOCIATION of PAINFUL and NON-PAINFUL COMORBIDITIES with CENTRAL MECHANISMS of KNEE PAIN.

    Walsh, David A (Annals of the Rheumatic Diseases, 2022-05)
    Background Central mechanisms of knee pain occur in the central nervous system and may intensify and prolong pain. Central pain mechanisms might be facilitated by ongoing nociceptive input. A link between multimorbidity and central mechanisms of knee pain is proposed; ongoing sensory inputs due to comorbidities may trigger changes in pain processing by the CNS. This might be particularly expected with painful comorbidities. Objectives To investigate potential relationships of painful and non-painful multimorbidity with central mechanisms of knee pain. Methods Cross-sectional analysis of self-report data from participants of the Investigating Musculoskeletal Health and Wellbeing cohort, who reported knee as their most bothersome site of joint pain over the previous month, with pain rated ≥1/10, and who had completed FRAIL and CAP-Knee (1) questionnaires. Two indirect measures suggesting central mechanisms involvement in knee pain were used as dependent variables; pain intensity (0-10 numerical rating scale) and CAP-Knee score (0-16 scale). Comorbidities were assigned either “painful comorbidity” or “non-painful comorbidity” status based on IASP classification of chronic pain criteria (2). Multivariable linear regression models, adjusted for age and sex, were employed to explore associations of comorbidity counts with pain intensity and CAP-Knee score. Results 736 participants satisfied inclusion criteria. 55% were female, mean age 71 (range 40 to 95). Painful comorbidity count and non-painful comorbidity count each had positive associations with pain intensity (β=0.42, 95% CI=0.29 to 0.54, p<0.001; and β=0.31, 95%CI=0.16 to 0.45, p<0.001, respectively). Painful and non-painful comorbidity counts each also were associated with CAP-Knee score (β=0.80, 95% CI=0.59 to 1.01, p<0.001; and β=0.52, 95% CI=0.27 to 0.77, p<0.001, respectively). Painful and non-painful comorbidity counts each remained significantly associated both with pain intensity and with CAP-Knee scores when both types of comorbidity count were included in the same multivariable model. Conclusion Both painful and non-painful comorbidities were positively associated with central mechanisms of knee pain, providing further insight into the interconnectedness of pain processing systems and the rest of the body. The explanation behind these relationships may depend on more than just ongoing nociceptive input. Future work should address possible contributions from genetic, pathophysiological, psychological, and pharmacological factors associated with comorbid diagnosis.
  • Validation of methods for converting the original Disease Activity Score (DAS) to the DAS28

    Walsh, David A (Rheumatology Internatiaonal, 2018-12)
    The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research. Different versions have been developed over the years to improve reliability and ease of use. Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses. As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable. Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate). DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas. Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement. The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale. A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision. A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.
  • Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts

    Walsh, David A (BMJ Open, 2019-05)
    Objectives: To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early rheumatoid arthritis (RA) inception cohorts with a focus on methotrexate (MTX) exposure. Design: Multicentre prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN). Setting: Secondary care, ERAS nine centres, ERAN 23 centres in England, Wales and Ireland. Participants: Patients with new diagnosis of RA, n=2701. Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3-6 months, at 12 months and annually thereafter. Primary and secondary outcome measures: Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA-specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis. Results: Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any conventional synthetic disease-modifying antirheumatic drug treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (OR 0.85, 95% CI 0.49 to 1.49, p=0.578) and a non-significant trend for delayed ILD diagnosis (OR 0.54, 95% CI 0.28 to 1.06, p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (OR 0.48, 95% CI 0.3 to 0.79, p=0.004) and longer time to ILD diagnosis (OR 0.41, 95% CI 0.23 to 0.75, p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first outpatient visit. Conclusions: MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may delay the onset of ILD.
  • Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population

    Walsh, David A (Osteoarthritis and Cartilage, 2019-03)
    Objective: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. Methods: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. Results: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. Conclusions: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.
  • Peripheral brain-derived neurotrophic factor contributes to chronic osteoarthritis joint pain

    Walsh, David A (Pain, 2020-01)
    Brain-derived neurotrophic factor (BDNF) and the high-affinity receptor tropomyosin receptor kinase B (TrkB) have important roles in neuronal survival and in spinal sensitization mechanisms associated with chronic pain. Recent clinical evidence also supports a peripheral role of BDNF in osteoarthritis (OA), with synovial expression of TrkB associated with higher OA pain. The aim of this study was to use clinical samples and animal models to explore the potential contribution of knee joint BDNF/TrkB signalling to chronic OA pain. Brain-derived neurotrophic factor and TrkB mRNA and protein were present in knee synovia from OA patients (16 women, 14 men, median age 67 years [interquartile range: 61-73]). There was a significant positive correlation between mRNA expression of NTRK2 (TrkB) and the proinflammatory chemokine fractalkine in the OA synovia. Using the surgical medial meniscal transection (MNX) model and the chemical monosodium iodoacetate (MIA) model of OA pain in male rats, the effects of peripheral BDNF injection, vs sequestering endogenous BDNF with TrkB-Fc chimera, on established pain behaviour were determined. Intra-articular injection of BDNF augmented established OA pain behaviour in MIA rats, but had no effect in controls. Intra-articular injection of the TrkB-Fc chimera acutely reversed pain behaviour to a similar extent in both models of OA pain (weight-bearing asymmetry MIA: -11 ± 4%, MNX: -12 ± 4%), compared to vehicle treatment. Our data suggesting a contribution of peripheral knee joint BDNF/TrkB signalling in the maintenance of chronic OA joint pain support further investigation of the therapeutic potential of this target.
  • Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network

    Walsh, David A (Reumatology, 2020-06)
    Objectives: To examine associations between function, quality of life and structural outcomes in patients achieving remission vs low disease activity in early RA. Methods: Demographic, clinical and radiographic variables were collected at baseline and then annually from the Early Rheumatoid Arthritis Study (ERAS) and Early Rheumatoid Arthritis Network (ERAN) inception cohorts in routine care from 1986 to 2012. Disease activity was categorized: mean DAS28 score between years 1 and 5: remission [mean remission DAS (mRDAS) <2.6] or low [mean low DAS (mLDAS) 2.6-3.2]; sustained low/remission DAS28 (sLDAS/sRDAS) at years 1 and 2; and sustained Boolean remission (sBR) at years 1 and 2. Changes in HAQ and Short Form 36 Health Survey Questionnaire [SF-36; physical (PCS) and mental (MCS) component score]) and total Sharp van der Heijde (SvdH) scores for each disease activity category were modelled using multi-level models. Covariates included year of onset, age, gender and DMARD use at first visit. Results: Of 2701 patients, 562 (21%) were categorized mRDAS, 330 (12%) mLDAS, 279 (10%) sRDAS, 203 (7.5%) sLDAS and 93 (3%) sBR. Patients categorized as mRDAS had increasingly divergent improved HAQ, SF-36 PCS, MCS and total SvdH scores compared with mLDAS (P-values 0.001 to <0.0001, all time points). Patients categorized as sRDAS had better HAQ, SF-36 PCS and MCS scores (P-values 0.05 to <0.0001, all time points) and SvdH scores (P = 0.05, years 3-5) over sLDAS. sBR was associated with better HAQ, and SF-36 PCS and MCS scores over sLDAS (P-values 0.002 to <0.0001, all time points). Conclusion: These findings from routine care support ACR/EULAR guidelines that remission is a preferable goal over low disease activity in early RA.
  • Predictors of response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: an individual patient data meta-analysis of randomised controlled trials

    Walsh, David A (Rheumatology, 2020-09)
    Objectives: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA. Methods: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction. Results: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity. Conclusion: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA.

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