Recent Submissions

  • The efficacy of systemic glucocorticosteroids for pain in rheumatoid arthritis: a systematic literature review and meta-analysis

    Walsh, David A (Rheumatology, 2022-01)
    Objectives Glucocorticosteroids (GCs) are recommended to suppress inflammation in people with active RA. This systematic review and meta-analysis aimed to quantify the effects of systemic GCs on RA pain. Methods A systematic literature review of randomized controlled trials (RCTs) in RA comparing systemic GCs to inactive treatment. Three databases were and spontaneous pain and evoked pain outcomes were extracted. Standardized mean differences (SMDs) and mean differences were meta-analysed. Heterogeneity (I2, tau statistics) and bias (funnel plot, Egger’s test) were assessed. Subgroup analyses investigated sources of variation. This study was pre-registered (PROSPERO CRD42019111562). Results A total of 18 903 titles, 880 abstracts and 226 full texts were assessed. Thirty-three RCTs suitable for the meta-analysis included 3123 participants. Pain scores (spontaneous pain) decreased in participants treated with oral GCs; SMD = −0.65 (15 studies, 95% CI −0.82, −0.49, P <0.001) with significant heterogeneity (I2 = 56%, P =0.0002). Efficacy displayed time-related decreases after GC initiation. Mean difference visual analogue scale pain was −15 mm (95% CI −20, −9) greater improvement in GC than control at ≤3 months, −8 mm (95% CI −12, −3) at >3–6 months and −7 mm (95% CI −13, 0) at >6 months. Similar findings were obtained when evoked pain outcomes were examined. Data from five RCTs suggested improvement also in fatigue during GC treatment. Conclusion Oral GCs are analgesic in RA. The benefit is greatest shortly after initiation and GCs might not achieve clinically important pain relief beyond 3 months. Treatments other than anti-inflammatory GCs should be considered to reduce the long-term burden of pain in RA.
  • Personal experience of osteoarthritis and pain questionnaires: Mapping Items to Themes

    Walsh, David A (Disability and Rehabilitation, 2014)
    Purpose: The aim of this study was to examine the correspondence between qualitative and quantitative methods of coding experience of pain reported by participants with osteoarthritis (OA) of the knee. Methods: A mapping grid was produced to record the correspondence between subthemes that emerged from thematic analysis of interviews with 24 participants with knee OA, and from questionnaire items which were used in a study of 192 knee OA participants. Items were rated according to their degree of correspondence between subthemes and questionnaire items, and an overall correspondence score was produced for each subtheme and questionnaire measure. Results: The subthemes that corresponded well with the questionnaire items were those that related to socio-emotional functioning, the overall experience of pain and the impact of pain on physical functioning. The questionnaire items did not relate to participants' knowledge about their condition and their experience of the medical system. Conclusions: The study indicated that many aspects of pain experience reported by patients in qualitative interviews are also assessed by commonly used questionnaire outcome measures for people with pain. However, although participants reported that knowledge about their condition and their experience of the medical system were important aspects of the overall pain experience, these are rarely used as outcome measures. Questionnaires that address these additional aspects of the pain experience could be useful to further evaluate the experience of pain and may help to address important concerns raised by patients with OA of the knee.
  • Cognitive and affective reassurance and patient outcomes in primary care: a systematic review

    Walsh, David A (Pain, 2013-11)
    In the context of uncertainty about aetiology and prognosis, good clinical practice commonly recommends both affective (creating rapport, showing empathy) and cognitive reassurance (providing explanations and education) to increase self-management in groups with nonspecific pain conditions. The specific impact of each of these components in reference to patients' outcomes has not been studied. This review aimed to systematically evaluate the evidence from prospective cohorts in primary care that measured patient-practitioner interactions with reference to patient outcomes. We carried out a systematic literature search and appraisal of study methodology. We extracted measures of affective and cognitive reassurance in consultations and their associations with consultation exit and follow-up measures of patients' outcomes. We identified 16 studies from 16,059 abstracts. Eight studies were judged to be high in methodological quality. Pooling could not be achieved as a result of heterogeneity of samples and measures. Affective reassurance showed inconsistent findings with consultation exit outcomes. In 3 high-methodology studies, an association was found between affective reassurance and higher symptom burden and less improvement at follow-up. Cognitive reassurance was associated with higher satisfaction and enablement and reduced concerns directly after the consultations in 8 studies; with improvement in symptoms at follow-up in 7 studies; and with reduced health care utilization in 3 studies. Despite limitations, there is support for the notion that cognitive reassurance is more beneficial than affective reassurance. We present a tentative model based on these findings and propose priorities for future research.
  • Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

    Walsh, David A (Annals of the Rheumatic Diseases, 2014-08)
    Background: Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). Objectives: To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Methods: Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Results: Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Conclusions: Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.
  • Augmented pain behavioural responses to intra-articular injection of nerve growth factor in two animal models of osteoarthritis

    Walsh, David A (Annals of the Rheumatic Diseases, 2014-09)
    Objectives: Nerve growth factor (NGF) is a promising analgesic target, particularly in osteoarthritis (OA) where existing therapies are inadequate. We hypothesised that pain responses to NGF are increased in OA joints. Here, NGF-evoked pain behaviour was compared in two rodent models of OA, and possible mechanisms underlying altered pain responses were examined. Methods: OA was induced in rat knees by meniscal transection (MNX) or intra-articular monosodium iodoacetate injection (MIA). Once OA pathology was fully established (day 20), we assessed pain behaviour (hindlimb weight-bearing asymmetry and hindpaw mechanical withdrawal thresholds) evoked by intra-articular injection of NGF (10 µg). Possible mechanisms underlying alterations in NGF-induced pain behaviour were explored using indomethacin pretreatment, histopathological evaluation of synovitis, and rtPCR for NGF receptor (tropomyosin receptor kinase (Trk)-A) expression in dorsal root ganglia (DRG). Results: Both the MIA and MNX models of OA displayed reduced ipsilateral weight bearing and hindpaw mechanical withdrawal thresholds, mild synovitis and increased TrkA expression in DRG. NGF injection into OA knees produced a prolonged augmentation of weight-bearing asymmetry, compared to NGF injection in non-osteoarthritic knees. However, hindpaw mechanical withdrawal thresholds were not further decreased by NGF. Pretreatment with indomethacin attenuated NGF-facilitated weight-bearing asymmetry and reversed OA-induced ipsilateral TrkA mRNA up-regulation. Conclusions: OA knees were more sensitive to NGF-induced pain behaviour compared to non-osteoarthritic knees. Cyclo-oxygenase products may contribute to increased TrkA expression during OA development, and the subsequent increased NGF sensitivity. Treatments that reduce sensitivity to NGF have potential to improve OA pain.
  • Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain.

    Walsh, David A (Annals of the Rheumatic Diseases, 2015-01)
    Objectives: Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. Methods: The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12-hydroxy-eicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. Results: We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ-17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ-17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. Conclusions: Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain.
  • Cannabinoid CB2 receptors regulate central sensitization and pain responses associated with osteoarthritis of the knee joint.

    Walsh, David A (PLoS One, 2013-11)
    Osteoarthritis (OA) of the joint is a prevalent disease accompanied by chronic, debilitating pain. Recent clinical evidence has demonstrated that central sensitization contributes to OA pain. An improved understanding of how OA joint pathology impacts upon the central processing of pain is crucial for the identification of novel analgesic targets/new therapeutic strategies. Inhibitory cannabinoid 2 (CB2) receptors attenuate peripheral immune cell function and modulate central neuro-immune responses in models of neurodegeneration. Systemic administration of the CB2 receptor agonist JWH133 attenuated OA-induced pain behaviour, and the changes in circulating pro- and anti-inflammatory cytokines exhibited in this model. Electrophysiological studies revealed that spinal administration of JWH133 inhibited noxious-evoked responses of spinal neurones in the model of OA pain, but not in control rats, indicating a novel spinal role of this target. We further demonstrate dynamic changes in spinal CB2 receptor mRNA and protein expression in an OA pain model. The expression of CB2 receptor protein by both neurones and microglia in the spinal cord was significantly increased in the model of OA. Hallmarks of central sensitization, significant spinal astrogliosis and increases in activity of metalloproteases MMP-2 and MMP-9 in the spinal cord were evident in the model of OA pain. Systemic administration of JWH133 attenuated these markers of central sensitization, providing a neurobiological basis for analgesic effects of the CB2 receptor in this model of OA pain. Analysis of human spinal cord revealed a negative correlation between spinal cord CB2 receptor mRNA and macroscopic knee chondropathy. These data provide new clinically relevant evidence that joint damage and spinal CB2 receptor expression are correlated combined with converging pre-clinical evidence that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic OA pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating OA pain.
  • Bone sialoprotein as a potential key factor implicated in the pathophysiology of osteoarthritis

    Walsh, David A (Osteoarthritis and Cartilage, 2014-04)
    Objective: We previously identified an association between bone sialoprotein (BSP) and osteoarthritic (OA) chondrocyte hypertrophy but the precise role of BSP in ostearthritis (OA) has not been extensively studied. This study aimed to confirm the association between BSP and OA chondrocyte hypertrophy, to define its effect on molecules produced by chondrocytes and to analyse its association with cartilage degradation and vascular density at the osteochondral junction. Method: Human OA chondrocytes were cultivated in order to increase hypertrophic differentiation. The effect of parathyroid hormone-related peptide (PTHrP), interleukin (IL)-1β or tumour necrosis factor (TNF)-α on BSP was analysed by real-time reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of BSP on OA chondrocytes production of inflammatory response mediators (IL-6, nitric oxide), major matrix molecule (aggrecan), matrix metalloprotease-3 and angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, IL-8, and thrombospondin-1) were investigated. BSP was detected by immunohistochemistry and was associated with cartilage lesions severity and vascular density. Results: PTHrP significantly decreased BSP, confirming its association with chondrocyte hypertrophy. In presence of IL-1β, BSP stimulated IL-8 synthesis, a pro-angiogenic cytokine but decreased the production of TSP-1, an angiogenesis inhibitor. The presence of BSP-immunoreactive chondrocytes in cartilage was associated with the severity of histological cartilage lesions and with vascular density at the osteochondral junction. Conclusion: This study supports the implication of BSP in the pathology of OA and suggests that it could be a key mediator of the hypertrophic chondrocytes-induced angiogenesis. To control chondrocyte hypertrophic differentiation is promising in the treatment of OA.
  • Hand and foot surgery rates in rheumatoid arthritis have declined from 1986 to 2011, but large-joint replacement rates remain unchanged: results from two UK inception cohorts

    Walsh, David A (Arthritis & Rheumatology, 2014-05)
    Objective: To assess whether there have been any secular changes in orthopedic interventions in patients with rheumatoid arthritis (RA) since 1986, as examined in 2 early rheumatoid arthritis (RA) inception cohorts with up to 25 years of followup. Methods: The study examined orthopedic data from the UK Early RA Study (1986-1999, 9 centers; n = 1,465) and the UK Early RA Network (2002-2012, 23 centers; n = 1,236) with linkage to national data sets (Hospital Episode Statistics, National Joint Registry, and Office of National Statistics). Clinical and laboratory measures and hand and foot radiographs were standardized and obtained yearly in both cohorts. The use of disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologic therapies reflected the contemporary conventional practices and guidelines of the time frames examined. Recruitment years were grouped into 6 periods, and interventions were classified into major, intermediate, and minor categories. Results: A total of 1,602 orthopedic surgical procedures were performed in 770 patients (29%) over a maximum of 25 years of followup. The 25-year cumulative incidence rate of major interventions was 21.7% (range 19.4-24.0%), and that of intermediate interventions was 21.5% (range 17.8-25.5%). There was a decline in the 10-year cumulative incidence of intermediate surgeries over time (P < 0.001), but not of major/minor surgery. This decline coincided with a gradual shift from sequential monotherapy to combination DMARD therapies and biologic agents in recent recruitment periods. Conclusion: Orthopedic surgery is an important and common outcome in RA. Only the rates of hand/foot surgery showed a consistent decline from 1986 to 2011. Possible explanations include differences in the pathophysiologic processes affecting the joints, variations in the responses to therapy between large-joint and small-joint destructive processes, and changes in service provision and thresholds for surgery over time.
  • Design, study quality and evidence of analgesic efficacy in studies of drugs in models of OA pain: a systematic review and a meta-analysis

    Walsh, David A (Osteoarthritis Cartilage, 2014-09)
    Objective: Studies using animal models are important in drug development, but often poorly predict treatment results in man. We investigated factors that may impact on the magnitude of the analgesic treatment effect in animal models of osteoarthritis (OA) pain. Design: Systematic review of studies that measured behavioural pain outcomes in small animal models of OA, and tested drugs which reduce OA pain in man. Standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated using random effects meta-analysis for selected models and drugs. Results: Most studies used rat models (42/50) and chemical methods of OA induction (39/50). Analgesic treatment effect (SMD) was most commonly measured between drug- and vehicle treated rats with knee OA. Meta-analysis was carried out for 102 such comparisons from 26 studies. The pooled SMD was 1.36 (95% CI = 1.15-1.57). Non-steroidal anti-inflammatory drugs (NSAIDs) were associated with smaller SMDs than opioids (z = -3.25, P = 0.001). Grip strength gave larger SMDs than assessment of static weight bearing (z = -4.60, P < 0.001), mechanically-evoked pain (z = -3.83, P = 0.001) and movement-evoked pain (z = -5.23, P < 0.001), and SMDs for mechanically-evoked pain were larger than for movement-evoked pain (z = -2.78, P = 0.006). Studies that reported structural evaluation of OA phenotype were associated with smaller SMDs (z = -2.45, P = 0.014). Publication was significantly biased towards positive findings. Conclusion: Attention to study-level moderators and publication bias may improve the ability of research using animal models to predict whether analgesic agents will reduce arthritis pain in man.
  • Pain phenotype in patients with knee osteoarthritis: classification and measurement properties of painDETECT and self-report Leeds assessment of neuropathic symptoms and signs scale in a cross-sectional study

    Walsh, David A (Arthritis Care & Research, 2015-04)
    Objective: Multiple mechanisms are involved in pain associated with osteoarthritis (OA). The painDETECT and Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) questionnaires screen for neuropathic pain and may also identify individuals with musculoskeletal pain who exhibit abnormal central pain processing. The aim of this cross-sectional study was to evaluate painDETECT and S-LANSS for classification agreement and fit to the Rasch model, and to explore their relationship to pain severity and pain mechanisms in OA. Methods: A total of 192 patients with knee OA completed questionnaires covering different aspects of pain. Another group of 77 patients with knee OA completed questionnaires and underwent quantitative sensory testing for pressure-pain thresholds (PPTs). Agreement between painDETECT and S-LANSS was evaluated using kappa coefficients and receiver operator characteristic (ROC) curves. Rasch analysis of both questionnaires was conducted. Relationships between screening questionnaires and measures of pain severity or PPTs were calculated using correlations. Results: PainDETECT and S-LANSS shared a stronger correlation with each other than with measures of pain severity. ROC curves identified optimal cutoff scores for painDETECT and S-LANSS to maximize agreement, but the kappa coefficient was low (κ = 0.33-0.46). Rasch analysis supported the measurement properties of painDETECT but not those of S-LANSS. Higher painDETECT scores were associated with widespread reductions in PPTs. Conclusion: The data suggest that painDETECT assesses pain quality associated with augmented central pain processing in patients with OA. Although developed as a screening questionnaire, painDETECT may also function as a measure of characteristics that indicate augmented central pain processing. Agreement between painDETECT and S-LANSS for pain classification was low, and it is currently unknown which tool may best predict treatment outcome.
  • The effect of disease severity and comorbidity on length of stay for orthopedic surgery in rheumatoid arthritis: Results from 2 UK inception cohorts, 1986-2012

    Walsh, David A (Journal of Rheumatology, 2015-05)
    Objective To examine factors predicting length of stay (LoS) for orthopedic intervention in rheumatoid arthritis (RA). Methods LoS for orthopedic intervention was examined in 2 consecutive, multicenter inception cohorts: the Early RA Study (n = 1465, 9 centers) and the Early RA Network (n = 1236, 23 centers). Date, type of orthopedic procedure, and LoS were recorded and validated against national data, the UK National Joint Registry, and the UK Hospital Episode Statistics database. Clinical, laboratory, and radiographic measures and comorbidity recorded at baseline and annually were examined for their predictive power on LoS using regression analysis. Results A total of 770 of 2701 patients (28.5%) had 1602 orthopedic interventions: 40% major (mainly total hip/knee replacements), 24% intermediate (mainly hand/wrist and ankle/foot surgery), and 16% minor (mainly soft tissue surgery). Median (interquartile range) LoS was 8 (5–13), 3 (1–5), and 1 (0–2) days for major, intermediate, and minor interventions, respectively. Older age predicted longer LoS (p < 0.001) whereas a more recent operation year predicted shorter LoS (p < 0.001). Markers of active disease, namely low hemoglobin, high Health Assessment Questionnaire, and high Disease Activity Scores in the first year all predicted longer LoS for all types of surgery (p = 0.001, p < 0.001, p = 0.05, respectively). Presence of 1 or more major comorbidities predicted longer LoS (p < 0.001). Conclusion Comorbidity and standard clinical and laboratory markers of disease activity affect the LoS for orthopedic surgery in RA, which has important clinical and economic implications, providing a target for improving patient outcomes.
  • . Long intergenic noncoding RNAs mediate the human chondrocyte inflammatory response and are differentially expressed in osteoarthritis cartilage

    Walsh, David A (Arthritis & Rheumatology, 2016-04)
    Objective: To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA. Methods: OA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non-OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and quantitative reverse transcriptase-polymerase chain reaction. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured with Luminex. Results: RNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, 183 of which had not previously been identified. Following interleukin-1β (IL-1β) stimulation, we identified 125 lincRNAs that were differentially expressed. The lincRNA p50-associated cyclooxygenase 2-extragenic RNA (PACER) and 2 novel chondrocyte inflammation-associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non-OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple proinflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL-1-stimulated secretion of proinflammatory cytokines. Conclusion: The inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs, including PACER, CILinc01, and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response, suggest that they may play an important role in mediating inflammation-driven cartilage degeneration in OA.
  • Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat

    Walsh, David A (Osteoarthritis and Cartilage, 2015-06)
    Objective: Although analgesic approaches targeting nerve growth factor (NGF) for the treatment of osteoarthritis (OA) pain remain of clinical interest, neurophysiological mechanisms by which NGF contribute to OA pain remain unclear. We investigated the impact of local elevation of knee joint NGF on knee joint, vs remote (hindpaw), evoked responses of spinal neurones in a rodent model of OA pain. Design: In vivo spinal electrophysiology was carried out in anaesthetised rats with established pain behaviour and joint pathology following intra-articular injection of monosodium iodoacetate (MIA), vs injection of saline. Neuronal responses to knee joint extension and flexion, mechanical punctate stimulation of the peripheral receptive fields over the knee and at a remote site (ipsilateral hind paw) were studied before, and following, intra-articular injection of NGF (10 μg/50 μl) or saline. Results: MIA-injected rats exhibited significant local (knee joint) and remote (lowered hindpaw withdrawal thresholds) changes in pain behaviour, and joint pathology. Intra-articular injection of NGF significantly (P < 0.05) increased knee extension-evoked firing of spinal neurones and the size of the peripheral receptive fields of spinal neurones (100% increase) over the knee joint in MIA rats, compared to controls. Intra-articular NGF injection did not significantly alter responses of spinal neurones following noxious stimulation of the ipsilateral hind paw in MIA-injected rats. Conclusion: The facilitatory effects of intra-articular injection of NGF on spinal neurones receiving input from the knee joint provide a mechanistic basis for NGF mediated augmentation of OA knee pain, however additional mechanisms may contribute to the spread of pain to remote sites.
  • Blocking the Tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis

    Walsh, David A (Annals of the Rheumatic Diseases, 2016-06)
    Objectives: Tropomyosin receptor kinase A (TrkA) mediates nociceptor sensitisation by nerve growth factor (NGF), but it is unknown whether selective TrkA inhibition will be an effective strategy for treating osteoarthritis (OA) pain. We determined the effects of a TrkA inhibitor (AR786) on pain behaviour, synovitis and joint pathology in two rat OA models. Methods: Knee OA was induced in rats by intra-articular monosodium-iodoacetate (MIA) injection or meniscal transection (MNX) and compared with saline-injected or sham-operated controls. Pain behaviour was assessed as weight-bearing asymmetry and paw withdrawal threshold to punctate stimulation. Oral doses (30 mg/kg) of AR786 or vehicle were administered twice daily in either preventive (day -1 to -27) or treatment (day 14-28) protocols. Effect maintenance was evaluated for 2 weeks after treatment discontinuation. Alterations in knee structure (cartilage, subchondral bone and synovium) were examined by macroscopic visualisation of articular surfaces and histopathology. Results: Preventive AR786 treatment inhibited pain behaviour development and therapeutic treatment attenuated established pain behaviour. Weight-bearing asymmetry increased 1 week after treatment discontinuation, but remained less than in vehicle-treated arthritic rats, whereas paw withdrawal thresholds returned to levels of untreated rats within 5 days of treatment discontinuation. AR786 treatment reduced MIA-induced synovitis and did not significantly affect osteochondral pathology in either model. Conclusions: Blocking NGF activity by inhibiting TrkA reduced pain behaviour in two rat models of OA. Analgesia was observed both using preventive and treatment protocols, and was sustained after treatment discontinuation. Selective inhibitors of TrkA therefore hold potential for OA pain relief.
  • Characterization of multinucleated giant cells in synovium and subchondral bone in knee osteoarthritis and rheumatoid arthritis

    Walsh, David A (BMC Musculoskeletal Disorders, 2015-08)
    Background: Multinucleated giant cells have been noticed in diverse arthritic conditions since their first description in rheumatoid synovium. However, their role in the pathogenesis of osteoarthritis (OA) or rheumatoid arthritis (RA) still remains broadly unknown. We aimed to study the presence and characteristics of multinucleated giant cells (MGC) both in synovium and in subchondral bone tissues of patients with OA or RA. Methods: Knee synovial and subchondral bone samples were from age-matched patients undergoing total joint replacement for OA or RA, or non-arthritic post mortem (PM) controls. OA synovium was stratified by histological inflammation grade using index tissue sections. Synovitis was assessed by Krenn score. Histological studies employed specific antibodies against macrophage markers or cathepsin K, or TRAP enzymatic assay. Results: Inflamed OA and RA synovia displayed more multinucleated giant cells than did non-inflamed OA and PM synovia. There was a significant association between MGC numbers and synovitis severity. A TRAP negative/cathepsin K negative Langhans-like subtype was predominant in OA, whereas both Langhans-like and TRAP-positive/cathepsin K-negative foreign-body-like subtypes were most commonly detected in RA. Plasma-like and foam-like subtypes also were observed in OA and RA synovia, and the latter was found surrounding adipocytes. TRAP positive/cathepsin K positive osteoclasts were only identified adjacent to subchondral bone surfaces. TRAP positive osteoclasts were significantly increased in subchondral bone in OA and RA compared to PM controls. Conclusions: Multinucleated giant cells are associated with synovitis severity, and subchondral osteoclast numbers are increased in OA, as well as in RA. Further research targeting multinucleated giant cells is warranted to elucidate their contributions to the symptoms and joint damage associated with arthritis.
  • Facet-joint injections for people with persistent non-specific low back pain (FIS): study protocol for a randomised controlled feasibility trial

    Walsh, David A (Health Technology Assessment, 2017-05)
    Background: The role of injections of therapeutic substances into the back as treatment for low back pain is unclear. Facet joint injections are widely used despite the absence of evidence of sustained benefit. We hypothesise that facet joint injections might facilitate engagement with physiotherapist-led, best usual care (a combined physical and psychological programme) and is a clinically and cost-effective treatment for people with suspected low back pain of facet joint origin. Methods/design: We present here the protocol for a randomised controlled feasibility trial for a main trial to test the above hypotheses. Patients referred to secondary care with persistent non-specific low back pain will be screened and invited to take part in the study. Those who meet the eligibility criteria will be invited for a physiotherapy assessment to confirm trial eligibility and for baseline data collection. All participants (n = 150) will be offered the best usual care package with physical and psychological components. Those randomised into the intervention arm (n = 75) will, in addition, receive intra-articular facet joint injections with local anaesthetic and steroids. Primary outcome data will be collected using daily and then weekly text messaging service for a pain score on a 0-10 scale. Questionnaire follow-up will be at 3, 6, and 12 months. Evaluation of trial processes and health economic analyses, including a value of information analysis, will be undertaken. The process evaluation will be mixed methods and will include the views of all stakeholders. Discussion: Whilst this trial is a feasibility study it is currently one of the largest trials in this area. The outcomes will provide some evidence on the use of facet joint injections for patients with clinically diagnosed facet joint pain.
  • Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

    Walsh, David A (Annals of the Rheumatic Diseases, 2015-06)
    Background: Patients with rheumatoid arthritis (RA) have an increased risk of certain solid cancers, in particular lung cancer, compared to the general population. Treatment with tumour necrosis factor (TNF) inhibitors (TNFi) may further enhance this risk. Objectives: To compare the risk of solid cancer in patients with RA treated with TNFi to that in patients treated with non-biologic (synthetic) disease modifying antirheumatic drugs (sDMARDs). Methods: Patients with a physician diagnosis of RA enrolled in the British Society for Rheumatology Biologics Register, a national prospective cohort study established in 2001 to monitor the long-term safety of TNFi, were followed via record linkage with the national cancer registries until first solid cancer, death, for 5 years, or until 2011. Rates of solid cancers in 11 767 patients without prior cancer who received TNFi were compared to those in 3249 patients without prior cancer treated with sDMARDs. Results: 427 solid cancers were reported in 52 549 patient-years follow-up for the TNFi group (81 (95% CI 74 to 89) per 10 000 patient-years) and 136 cancers were reported in 11 672 patient-years in the sDMARD cohort (117 (95% CI 98 to 138) per 10 000 patient-years). After adjusting for differences in baseline characteristics there was no difference in risk of solid cancer for TNFi compared to sDMARD treated patients: HR 0.83 (95% CI 0.64 to 1.07). There was no difference in the relative risk of cancer for any of the individual TNFi drugs. Conclusions: The addition of TNFi to sDMARD does not alter the risk of cancer in RA patients selected for TNFi in the UK.
  • Reliability and responsiveness of measures of pain in people with osteoarthritis of the knee; a psychometric evaluation

    Walsh, David A (Disability and Rehabilitation, 2017-04)
    Purpose: To examine the fit between data from the Short Form McGill Pain Questionnaire (SF-MPQ-2) and the Rasch model, and to explore the reliability and internal responsiveness of measures of pain in people with knee osteoarthritis. Methods: Participants with knee osteoarthritis completed the SF-MPQ-2, Intermittent and Constant Osteoarthritis Pain questionnaire (ICOAP) and painDETECT. Participants were sent the same questionnaires 3 and 6 months later. Results: Fit to the Rasch model was not achieved for the SF-MPQ-2 Total scale. The Continuous subscale yielded adequate fit statistics after splitting item 10 on uniform DIF for gender, and removing item 9. The Intermittent subscale fit the Rasch model after rescoring items. The Neuropathic subscale had relatively good fit to the model. Test-retest reliability was satisfactory for most scales using both original and Rasch scoring ranging from fair to substantial. Effect sizes ranged from 0.13 to 1.79 indicating good internal responsiveness for most scales. Conclusions: These findings support the use of ICOAP subscales as reliable and responsive measure of pain in people with knee osteoarthritis. The MPQ-SF-2 subscales found to be acceptable alternatives. Implications for Rehabilitation The McGill Pain Questionnaire short version 2 is not a unidimensional scale in people with knee osteoarthritis, whereas three of the subscales are unidimensional. The McGill Pain Questionnaire short version 2 Affective subscale does not have good measurement properties for people with knee osteoarthritis. The McGill Pain Questionnaire short version 2 and the Intermittent and Constant Osteoarthritis Pain scales can be used to assess change over time. The painDETECT performs better as a screening measure than as an outcome measure.
  • Identifying placebo responders and predictors of response in osteoarthritis: a protocol for individual patient data meta-analysis

    Walsh, David A (Systematic Reviews, 2016-10)
    Background: The management of osteoarthritis (OA) is unsatisfactory, as most treatments are not clinically effective over placebo and most drugs have considerable side effects. On average, 75 % of the analgesic effect from OA treatments in clinical trials can be attributed to a placebo response, and this response varies greatly from patient to patient. This individual patient data (IPD) meta-analysis aims to identify placebo responders and the potential determinants of the placebo response in OA. Methods: This study is undertaken in conjunction with the OA Trial Bank, an ongoing international consortium aiming to collect IPD from randomised controlled trials (RCTs) for all treatments of OA. RCTs for each treatment of OA have been systematically searched for, and authors of the relevant trials have been contacted to request the IPD. We will use the IPD of placebo-controlled RCTs held by the OA Trial Bank for this project. The IPD in placebo groups will be used to investigate the placebo response according to the minimum clinically important difference (MCID) threshold (e.g. 20 % pain reduction). Responders to placebo will be compared with non-responders to identify predictors of response. The quality of the trials will be assessed and potential determinants will be examined using multilevel logistic regression analyses. Discussion: This study explores the varying magnitude of the placebo response and the proportion of participants that experience a clinically important placebo effect in OA RCTs. Potential determinants of the placebo response will also be investigated. These determinants may be useful for future studies as it may allow participants to be stratified into groups based on their likely response to placebo. The results of this study may also be useful for pharmaceutical companies, who could improve the design of their studies in order to separate the specific treatment from the non-specific contextual (i.e. placebo) effects.

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