Discordance between pain and inflammation in rheumatoid arthritis

Recent research interest has focused on the continuing problem of pain in RA. The long term prognosis for pain could be improved, even when inflammation is being suppressed. This talk will describe the progression of pain, and examine how factors other than inflammation may contribute to the prognosis of symptoms in people with RA. The DAS28 components have been used to try and quantify non-inflammatory pain mechanisms. The research examining this will also be summarised

Mild acetabular dysplasia and risk of osteoarthritis of the hip : a case-control study

Objective To determine whether mild variation in acetabular depth (AD) and shape is a risk factor for osteoarthritis (OA) of the hip. Methods The unaffected contralateral hip of patients with unilateral hip OA was compared with hips of asymptomatic controls without hip OA, derived from the Nottingham Genetics Osteoarthritis and Lifestyle case–control study. Standardised anteroposterior x-rays of the pelvis were used to measure centre edge (CE) angle and AD. Cut-off points for narrow CE angle and shallow AD were calculated from the control group (mean −1.96×SD). The relative risk of hip OA associated with each feature was estimated using OR and 95% CI and adjusted risks were calculated by logistic regression. Results In controls, both the CE angle and the AD were lower in the left hip than in the right hip. The CE angle related to age in both hips, and AD of the right hip was lower in men than in women. The contralateral unaffected hip in patients with unilateral hip OA had a decreased CE angle and AD compared with controls, irrespective of side. The lowest tertile of the CE angle in contralateral hips was associated with an eightfold risk of OA (aOR 8.06, 95% CI 4.87 to 13.35) and the lowest tertile of AD was associated with a 2.5-fold risk of OA (aOR 2.53, 95% CI 1.28 to 5.00). Significant increases in the risk of OA were also found as the CE angle and AD decreased

Disease activity flares and pain flares in an early rheumatoid arthritis inception cohort; characteristics, antecedents and sequelae

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: RA flares are common and disabling. They are described in terms of worsening inflammation but pain and inflammation are often discordant. To inform treatment decisions, we investigated whether inflammatory and pain flares are discrete entities. Methods: People from the Early RA Network (ERAN) cohort were assessed annually up to 11 years after presentation (n = 719, 3703 person-years of follow up). Flare events were defined in 2 different ways that were analysed in parallel; DAS28 or Pain Flares. DAS28 Flares satisfied OMERACT flare criteria of increases in DAS28 since the previous assessment (≥1.2 points if active RA or ≥ 0.6 points if inactive RA). A ≥ 4.8-point worsening of SF36-Bodily Pain score defined Pain Flares. The first documented episode of each of DAS28 and Pain Flare in each person was analysed. Subgroups within DAS28 and Pain Flares were determined using Latent Class Analysis. Clinical course was compared between flare subgroups. Results: DAS28 (45%) and Pain Flares (52%) were each common but usually discordant, with 60% of participants in DAS28 Flare not concurrently in Pain Flare, and 64% of those in Pain Flare not concurrently in DAS28 Flare. Three discrete DAS28 Flare subgroups were identified. One was characterised by increases in tender/swollen joint counts (14.4%), a second by increases in symptoms (13.1%), and a third displayed lower flare severity (72.5%). Two discrete Pain Flare subgroups were identified. One occurred following low disease activity and symptoms (88.6%), and the other occurred on the background of ongoing active disease and pain (11.4%). Despite the observed differences between DAS28 and Pain Flares, each was associated with increased disability which persisted beyond the flare episode. Conclusion: Flares are both common and heterogeneous in people with RA. Furthermore our findings indicate that for some patients there is a discordance between inflammation and pain in flare events. This discrete flare subgroups might reflect different underlying inflammation and pain mechanisms. Treatments addressing different mechanisms might be required to reduce persistent disability after DAS28 and Pain Flares.Peer reviewedFinal Published versio

Pain mechanisms in rheumatoid arthritis

Understanding of the causes and underlying mechanisms of pain in people with RA is rapidly changing. With the advent of more effective disease modifying drugs, joint inflammation is becoming a more treatable cause of pain, and joint damage can often be prevented. However, the long-term prognosis for pain still is often unfavourable, even after inflammation is suppressed. Pain is associated with fatigue and psychological distress, and RA pain qualities often share characteristics with neuropathic pain. Each of these characteristics suggests key roles for central neuronal processing in RA pain. Pain processing by the central nervous system can maintain and augment RA pain, and is a promising target for future treatments. Inflammatory mediators, such as cytokines, may provoke central pain sensitisation in animal models, and both local and systemic inflammation might contribute to central pain augmentation in RA. Controlled trials of treatments that target central pain processing have shown some benefit in people with RA, and might be most effective in individuals for whom central pain augmentation plays a key role. For people with RA who experience persistent pain, identifying underlying pain mechanisms critically determines the balance between escalation of anti-inflammatory and disease-modifying treatments and other strategies to provide symptomatic analgesia

Associations of symptomatic knee OA with histopathologic features in subchondral bone

© 2019, American College of Rheumatology Objective: Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA. Methods: Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase–positive subchondral osteoclasts, and synovitis were compared between groups. Results: Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups. Conclusion: Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA

A cross-sectional study of pain sensitivity, disease-activity assessment, mental health, and fibromyalgia status in rheumatoid arthritis

INTRODUCTION: Pain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA. METHODS: In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status. RESULTS: More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health. CONCLUSIONS: Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled

Discrete trajectories of resolving and persistent pain in people with rheumatoid arthritis despite undergoing treatment for inflammation: results from three UK cohorts

Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesised that discrete RA subgroups might display favourable or unfavourable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation.Growth Mixture Modelling was used to identify discrete trajectories of SF36-Bodily Pain scores during 3 years in 3 RA cohorts (Early RA Network (ERAN); n=683, British Society for Rheumatology Biologics Register Biologics (n=7090) and Non-Biologics (n=1720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years.Mean SF36-Bodily Pain scores in each cohort improved but remained throughout 3y follow up >1 SD worse than the UK general population average. Discrete Persistent Pain (59% to 79% of cohort participants) and Resolving Pain (19% to 27%) trajectories were identified in each cohort. In ERAN, a third trajectory displaying persistently Low Pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% of them were found to follow a Persistent Pain trajectory. When trajectories were compared, greater disability (aORs 2.3-2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (aORs 1.6-1.8) were risk factors for Persistent Pain trajectories in each cohort.In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during RA treatment. Inflammation does not fully explain the pain trajectories, and non-inflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long term burden of arthritis pain

Association of subchondral bone marrow lesion localization with weight-bearing pain in people with knee osteoarthritis: data from the Osteoarthritis Initiative

© 2021, The Author(s). Background: Subchondral bone marrow lesions (BMLs) detected on MRI in knee osteoarthritis (OA) are associated with knee pain. The prevalence and progression of subchondral BMLs are increased by mechanical knee load. However, associations of subchondral BML location with weight-bearing knee pain are currently unknown. In this study, we aim to demonstrate associations of subchondral BML location and size with weight-bearing knee pain in knee OA. Methods: We analyzed 1412 and 582 varus knees from cross-sectional and longitudinal Osteoarthritis Initiative datasets, respectively. BML scores were semi-quantitatively analyzed with the MRI Osteoarthritis Knee Score for 4 subchondral regions (median and lateral femorotibial, medial and lateral patellofemoral) and subspinous region. Weight-bearing and non-weight-bearing pain scores were derived from WOMAC pain items. Correlation and negative binomial regression models were used for analysis of associations between the BML scores and pain at baseline and changes in the BML scores and changes in pain after 24-month follow-up. Results: Greater BML scores at medial femorotibial and lateral patellofemoral compartments were associated with greater weight-bearing pain scores, and statistical significance was retained after adjusting for BML scores at the other 4 joint compartments and other OA features, as well as for non-weight-bearing pain, age, sex, and body mass index (BMI) (medial femorotibial; B = 0.08, p = 0.02. patellofemoral; B = 0.13, p = 0.01). Subanalysis revealed that greater medial femorotibial BML scores were associated with greater pain on walking and standing (B = 0.11, p = 0.01, and B = 0.10, p = 0.04, respectively). Lateral patellofemoral BML scores were associated with pain on climbing, respectively (B = 0.14, p = 0.02). Increases or decreases over 24 months in BML score in the medial femorotibial compartment were significantly associated with increases or decreases in weight-bearing pain severity after adjusting for non-weight-bearing pain, age, sex, baseline weight-bearing pain, BMI, and BML at the other 4 joint compartments (B = 0.10, p = 0.01). Conclusions: Subchondral BML size at the medial femorotibial joint compartment was specifically associated with the severity and the change in weight-bearing pain, independent of non-weight-bearing pain, in knee OA. Specific associations of weight-bearing pain with subchondral BMLs in weight-bearing compartments of the knee indicate that BMLs in subchondral bone contribute to biomechanically induced OA pain

Prediction of persistent knee pain by pressure pain detection thresholds: results from the Knee Pain In the Community cohort (KPIC)

Background: Knee pain results from a combination of nociceptive input from the joint, and processing by the central nervous system. Pressure pain detection thresholds (PPTs) are lower and pain is more severe in people with greater central sensitisation. Objective: We hypothesised that lower PPTs predicted worse pain prognosis in people with knee pain. Methods: KPIC participants were people aged >40 years recruited from Nottingham, UK. Participants were mailed questionnaires at baseline and 1 year. This study reports a sample of responders who attended baseline and 1 year clinical assessment, had self-reported knee pain (within the last 4 weeks) and underwent PPT. PPTs were measured at the knee, anterior tibia and the sternum. Radiographic knee OA was classified using an atlas. Questionnaires measured ICOAP (constant and intermittent knee pain), painDETECT (neuropathic-like) and average knee pain severity over 4 weeks (0-10). The presence of pain at baseline and 1 year (persistent pain), or pain severity were predicted from baseline anterior tibia PPT. Additional analyses adjusted for baseline pain score, age, sex, BMI, or for radiographic knee OA. Pain persistence (Yes/No) was analysed using t tests, odds ratios (OR) and logistic regression. Pain severity was analysed using linear regression. Results: The sample for this study contained n=419 people at baseline, and n=182 people reported knee pain persistent over both time points. The mean (SD) values were age 61 (9) years, BMI 30.1 (5.8) kg m-2, 59% female, and 36% fulfilled radiographic OA criteria at the index knee, for those with persistent knee pain at 1 year. In univariate analysis, persistent knee pain was associated with a lower PPT at baseline (461 vs 424 kPa; OR (95% CI) 0.58 (0.34-0.97) p=0.020). Adjustments for age, sex and BMI removed the significance from the association (adjusted OR (95% CI) 0.64 (0.36-1.13) p=0.120). In those with persistent pain, worse 1 year ICOAP-constant, ICOAP-intermittent, painDETECT and knee pain severity were correlated with lower baseline anterior tibia PPT ( r= -0.28 to -0.24; p<0.004). After adjustment for baseline pain, 1 year ICOAP-constant pain scale was significantly predicted by baseline PPT (B (95% CI), -1.05 (-1.91 to -0.20) p=0.016). Linear regression with adjustments for age, sex and BMI also indicated that baseline PPT predicted worse ICOAP-constant pain (B (95% CI)-0.99 (-1.94 to -0.04) p=0.041). The presence of radiographic OA at baseline was not significantly associated with PPT at baseline. Adjustment for baseline radiographic OA did not remove the association between baseline PPT and ICOAP-constant at 1 year (anterior tibia PPT -1.04 (-1.89 to -0.18) p=0.018). PPT at joint lines or sternum displayed similar patterns of association with 1 year pain as did PPT at the anterior tibia. Conclusions: Pressure pain detection thresholds suggestive of central sensitisation at baseline were associated with knee pain prognosis at 1 year, in particular with constant knee pain. The presence of radiographic OA also predicted 1 year pain prognosis, independent of PPT

Reductions in radiographic progression in early RA over 25-years: changing contribution from RF in 2 multi-centre UK inception cohorts

Objectives: To assess 5-year progression of erosions and Joint Space Narrowing (JSN), and their associations with RF status in two large, multi-centre early-RA cohorts spanning 25-years. Methods: Radiographic joint damage was recorded using the Sharp/van der Heijde (SvdH) method in the Early RA Study (ERAS) 1986-2001, and the Early RA Network (ERAN) 2002-2013. Mixed-effects negative-binomial regression estimated changes in radiographic damage over 5-years, including erosions and JSN separately. Rheumatoid Factor (RF), along with age, sex and baseline markers of disease activity were controlled for. Results: 1,216 patients from ERAS and 446 from ERAN had radiographic data. Compared to ERAS, ERAN patients had a lower mean total SvdH score at baseline (ERAN=6.2 vs. ERAS=10.5, p<0.001), and mean annual rate of change (ERAN=2.5 vs. ERAS=6.9 per year, p<0.001). 74% of ERAS and 27% of ERAN patients progressed ≥5 units. Lower scores at baseline in ERAN were largely driven by reductions in JSN (ERAS=3.9 vs. ERAN=1.2, p<0.001), along with erosions (ERAS=1.9 vs. ERAN=0.8, p<0.001). RF was associated with greater progression in each cohort, but the absolute difference in mean annual rate of change for RF positive patients was substantially higher for ERAS (RF+= 8.6 vs. RF-= 5.1, p<0.001), relative to ERAN (RF+= 2.0 vs. RF-= 1.9, p=0.855). Conclusion: Radiographic progression has significantly reduced between the two cohorts, associated with lower baseline damage and other factors, including changes in early DMARD use. The impact of RF status as a prognostic marker of clinically meaningful change in radiographic progression has markedly diminished in the context of more modern treatment. This article is protected by copyright. All rights reserved