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.

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.

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.

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.

TL]) or modified (MMTL left intact, transection of the coronary ligaments) DMM surgery, or sham surgery. Adult male Sprague Dawley rats (n = 76, weight 175-199g) underwent either modified meniscal transection (MMNX) surgery (transection of the medial meniscus whilst the medial collateral ligament is left intact) or sham surgery. Pain behaviours (weight bearing asymmetry [in mice and rats] and paw withdrawal thresholds [in rats]) were measured pre-surgery and weekly up to 16 weeks post-surgery. Post-mortem knee joints were scored for cartilage damage, synovitis, and osteophyte size. There was a significant increase in weight bearing asymmetry from 13 weeks following traditional, but not modified, DMM surgery when compared to sham operated mice. Both traditional and modified DMM surgery led to similar joint pathology. There was significant pain behaviour from 6 weeks following MMNX model compared to sham operated control rats. Synovitis was significant 4 weeks after MMNX surgery, whereas significant chondropathy was first evident 8 weeks post-surgery, compared to sham controls. Pain behaviour is not always present despite significant changes in medial tibial plateau cartilage damage and synovitis, reflecting the heterogeneity seen in human OA. The development of a slowly progressing surgical model of OA pain in the rat suggests that synovitis precedes pain behaviour and that chondropathy is evident later, providing the foundations for future mechanistic studies into the disease.

The aim of this study was to compare the relationship between two health outcomes (pain and self-reported health) and personality while accounting for heterogeneity in arthritic disease. Traditionally health research has treated patients' disease experiences as homogeneous but stratified medicine suggests that doing so might over-generalise findings and miss important effects. We present a longitudinal analysis over 14 years, on a subsample of 443 arthritic respondents from the English Longitudinal Study of Ageing (ELSA). Using linear regressions, we modelled how the Big Five domains of personality (wave 5) moderated the relationship between past (at wave 1) and present health (at wave 7). Then, to model heterogeneity in arthritis experience we included assignment to 4 different sub-groups based on their experience of pain progression. The results showed that modelling heterogeneity led to the identification of specific stratified effects for personality (neuroticism, agreeableness, and extraversion) not observed when these data are treated as homogenous. Higher agreeableness was associated with worse pain for those in a sub-group reporting the greatest pain, and higher extraversion was protective against pain among those whose pain improved. The results highlight the importance of modelling heterogeneity of disease.

Objective: To assess the long-term safety and 16-week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA). Methods: This was a phase III randomized, double-blind, active treatment-controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56-week treatment/24-week posttreatment follow-up) in adults who were receiving stable-dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals [95% CIs]) were calculated. Results: Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time-adjusted rate/1,000 patient-years 38.3 [95% CI 28.0, 52.5] and 71.5 [95% CI 56.7, 90.2], respectively, versus 14.8 [95% CI 8.9, 24.6]; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant. Conclusion: In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks.

Background: Several pharmaceutical treatments for chronic pain caused by osteoarthritis (OA) and chronic low back pain (CLBP) are available or currently under development, each associated with different adverse events (AEs) and efficacy profiles. It is therefore important to understand what trade-offs patients are willing to make when choosing between treatments. Methods: A discrete-choice experiment (DCE) was conducted with 437 adults with chronic pain caused by OA and/or CLBP. Respondents were presented with a series of scenarios and asked to choose between pairs of hypothetical treatments, each defined by six attributes: level of symptom control; risks of heart attack, rapidly progressive osteoarthritis and dependency; frequency and mode of administration and cost. Attributes were based on known profiles of oral nonsteroidal anti-inflammatory drugs, opioids and injected nerve growth factor inhibitors, the last of which were under clinical development at the time of the study. Data were analysed using a latent class (LC) model to explore preference heterogeneity. Results: Overall, respondents considered improving symptom control and reducing risk of physical dependency to be the most important attributes. The LC analysis identified four participant classes: an 'efficacy-focused' class (33.7%), a 'cost-averse' class (29.4%), a 'physical-dependence-averse' class (19.6%) and a 'needle-averse' class (17.3%). Subgroup membership was incompletely predicted by participant age and their responses to comprehension questions. Conclusions: Preference heterogeneity across respondents indicates a need for a personalized approach to offering treatment options. Symptom improvement, cost, physical dependence and route of administration might be important to different patients. Significance: Multiple treatment options that differ substantially in terms of efficacy and adverse events are available for the management of chronic pain. With a growing emphasis on a patient-centred care model that incorporates patients' priorities and values into treatment decisions, there is a need to understand how individuals with chronic musculoskeletal pain balance the benefits and risks of treatment and how treatment priorities vary among individuals. This study was designed to identify patient preferences for different characteristics of treatments for the management of chronic pain and to investigate how preferences differ among respondents.

Purpose of review: Much has been documented in recent years on the possible involvement of angiogenesis in osteoarthritis. An understanding of the various regulatory mechanisms controlling blood vessel growth in the joint should lead to novel therapeutics, which selectively inhibit undesirable angiogenesis. Here, we summarize recent findings on the roles of angiogenesis in osteoarthritis and place this evidence in the context of previous literature in order to help explain pain and disease progression. Recent findings: Inflammation and angiogenesis are closely associated in osteoarthritis, modulating functions of chondrocytes, contributing towards abnormal tissue growth and perfusion, ossification and endochondral bone development, leading to radiographic changes observed in the joint. Innervation accompanies vascularization and inflammation, hypoxia and mechanical overload are all thought to contribute in sensitizing these new nerves leading to increased pain. Articular cartilage provides a unique environment in which blood vessel growth is regulated by endogenous angiogenesis inhibitors and matrix constituents, as well as by growth factors produced by chondrocytes, subchondral bone and synovium. MRI and ultrasound enable the in-vivo visualization of abnormal vascularity in synovium and subchondral bone that have not been apparent with conventional radiography. As a result of these new findings, the widely accepted notion that osteoarthritis is primarily a disease of the cartilage is being challenged. Summary: Molecular mechanisms and consequences of angiogenesis in osteoarthritis are slowly being elucidated. Studies, both in humans and animal models, support the notion that inhibiting angiogenesis will provide effective therapeutic strategies for treating osteoarthritis. Better techniques that can more precisely visualize the vascular changes of the whole joint can further enhance our understanding of osteoarthritis, and can provide proof of concept and early evidence of efficacy in trials of novel therapeutic interventions.

Osteoarthritis (OA) is a major cause of pain and disability in the aging population, but its pathogenesis remains incompletely understood. Alterations beneath the articular cartilage at the osteochondral junction are attracting interest as possible mediators of pain and structural progression in OA. Osteochondral changes occur early during the development of OA and may aggravate pathology elsewhere in the joint. Loss of osteochondral integrity removes the barrier between intra-articular and subchondral compartments, exposing subchondral bone and its nerves to abnormal chemical and biomechanical influence. Osteochondral plasticity results in a merging of tissue compartments across the junction. Loss of the clearly differentiated demarcation between bone and articular cartilage is associated with invasion of articular cartilage by blood vessels and sensory nerves, and advancing endochondral ossification. Increased subchondral bone turnover is intimately associated with these alterations at the osteochondral junction. Cells signal across the osteochondral junction, and this cross-talk may be both a consequence of, and contribute to these pathological changes. Bone turnover, angiogenesis and nerve growth are also features of other diseases such as osteoporosis and cancers, for which therapeutic interventions are already advanced in their development. Here we review pathological changes at the osteochondral junction and explore their potential therapeutic implications for OA. This article is part of a Special Issue entitled "Osteoarthritis".