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

A systematic correlation between two-dimensional flow topology and the abstract statistics of turbulence

Velocity differences in the direct enstrophy cascade of two-dimensional turbulence are correlated with the underlying flow topology. The statistics of the transverse and longitudinal velocity differences are found to be governed by different structures. The wings of the transverse distribution are dominated by strong vortex centers, whereas, the tails of the longitudinal differences are dominated by saddles. Viewed in the framework of earlier theoretical work this result suggests that the transfer of enstrophy to smaller scales is accomplished in regions of the flow dominated by saddles.Comment: 4 pages, 4 figure

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

Estimating dominant runoff modes across the conterminous United States

Effective natural resource planning depends on understanding the prevalence of runoff generating processes. Within a specific area of interest, this demands reproducible, straightforward information that can complement available local data and can orient and guide stakeholders with diverse training and backgrounds. To address this demand within the contiguous United States (CONUS), we characterized and mapped the predominance of two primary runoff generating processes: infiltration‐excess and saturation‐excess runoff (IE vs. SE, respectively). Specifically, we constructed a gap‐filled grid of surficial saturated hydraulic conductivity using the Soil Survey Geographic and State Soil Geographic soils databases. We then compared surficial saturated hydraulic conductivity values with 1‐hr rainfall‐frequency estimates across a range of return intervals derived from CONUS‐scale random forest models. This assessment of the prevalence of IE versus SE runoff also incorporated a simple uncertainty analysis, as well as a case study of how the approach could be used to evaluate future alterations in runoff processes resulting from climate change. We found a low likelihood of IE runoff on undisturbed soils over much of CONUS for 1‐hr storms with return intervals \u3c5 years. Conversely, IE runoff is most likely in the Central United States (i.e., Texas, Louisiana, Kansas, Missouri, Iowa, Nebraska, and Western South Dakota), and the relative predominance of runoff types is highly sensitive to the accuracy of the estimated soil properties. Leveraging publicly available data sets and reproducible workflows, our approach offers greater understanding of predominant runoff generating processes over a continental extent and expands the technical resources available to environmental planners, regulators, and modellers