Pain Mechanism in Rheumatoid Arthritis: From Cytokines to Central Sensitization
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SUBMITTER: Cao Y
PROVIDER: S-EPMC7503123 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectivePain sensitization may contribute to pain severity in rheumatoid arthritis (RA), impacting disease activity assessment. We examined whether pain processing mechanisms were associated with disease activity among RA patients with active disease.MethodsThe study included 139 subjects enrolled in the Central Pain in Rheumatoid Arthritis cohort. Subjects underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at multiple sites, conditioned pain modulation, and temporal summation. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI) and its components. We examined cross-sectional associations between QST measures and disease activity using linear regression.ResultsLow PPTs (high pain sensitization) at all sites were associated with high CDAI scores (P ≤ 0.03) and tender joint counts (P ≤ 0.002). Associations between PPTs and patient global assessments were also seen at most sites. High temporal summation at the forearm (also reflecting high pain sensitization) was significantly associated with high CDAI scores (P = 0.02), patient global assessment scores (P = 0.0006), evaluator global assessment scores (P = 0.01), and tender joint counts (P = 0.02). Conversely, conditioned pain modulation (a measure of descending inhibitory pain pathways) was associated only with tender joint count (P = 0.03).ConclusionHigh pain sensitization is associated with elevations in disease activity measures. Longitudinal studies are underway to elucidate the cause-effect relationships between pain sensitization and inflammatory disease activity in RA.
| S-EPMC5654691 | biostudies-literature
Project description:BackgroundPain and fatigue are persistent problems in people with rheumatoid arthritis. Central sensitisation (CS) may contribute to pain and fatigue, even when treatment has controlled inflammatory disease. This study aims to validate a self-report 8-item questionnaire, the Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA) questionnaire, developed to measure central pain mechanisms in RA, and to predict patient outcomes and response to treatment. A secondary objective is to explore mechanisms linking CS, pain and fatigue in people with RA.Methods/designThis is a prospective observational cohort study recruiting 250 adults with active RA in secondary care. The CAP-RA questionnaire, demographic data, medical history, and patient reported outcome measures (PROMs) of traits associated with central sensitization will be collected using validated questionnaires. Quantitative sensory testing modalities of pressure pain detection thresholds, temporal summation and conditioned pain modulation will be indices of central sensitization, and blood markers, swollen joints and ultrasound scans will be indices of inflammation. Primary data collection will be at baseline and 12 weeks. The test-retest reliability of CAP-RA questionnaire will be determined 1 week after the baseline visit. Pain and fatigue data will be collected weekly via text messages for 12 weeks. CAP-RA psychometric properties, and predictive validity for outcomes at 3 months will be evaluated.DiscussionThis study will validate a simple self-report questionnaire against psychophysical indices of central sensitization and patient reported outcome measures of traits associated with CS in a population of individuals with active RA. The application of this instrument in the clinical environment could provide a mechanism-based stratification tool to facilitate the provision of targeted therapy to individuals with pain and fatigue in RA, alongside treatments that target joint inflammation.Trial registrationClinicaltrials.gov NCT04515589 . Date of registration 17 August 2020.
| S-EPMC8223274 | biostudies-literature
Project description:OBJECTIVES:To test whether central sensitization was associated with greater fatigue, independently of musculoskeletal pain. METHODS:2477 prospective cohort study participants completed a baseline questionnaire comprising the Chalder Fatigue Scale (CFQ), pain, demographics, physical activity, anxiety, depression and medication use. In a clinical assessment of 290 (11.7%) participants, central sensitization was measured by the wind-up ratio test at the hand (WUR-H) and foot (WUR-F). Bioelectric impedance determined proportion body fat. All participants were followed up 12 months later, at which time they completed the CFQ. Linear regression, with inverse probability sampling weights, tested the relationship between WUR at baseline and CFQ at 12 months, adjusted for baseline CFQ, demographics, lifestyle factors, mental health and baseline pain. RESULTS:At baseline, the median interquartile range WUR-H and WUR-F were similar (2.3 (1.5, 4.0) and 2.4 (1.6, 3.9) respectively) and did not differ by sex (difference WUR-H: -0.29, 95% confidence interval -1.28-0.71; WUR-F: -0.57 (-1.50-0.36) or age(WUR-H: -0.53, -1.49-0.43; WUR-F:-0.08, -0.98-0.82). WUR-H scores (β = 0.11, 95% confidence interval: 0.07-0.16) and WUR-F scores (0.13, 0.08-0.17) were positively associated with CFQ scores at follow-up, independently of baseline CFQ and other covariates. These associations were not explained by baseline pain. CONCLUSION:Fatigue was predicted by central sensitization, independently of the presence of pain. For those seeking to treat fatigue, the benefit of interventions that reduce central sensitization should be investigated.
| S-EPMC6812719 | biostudies-literature
Project description:Pain, the primary symptom of osteoarthritis (OA), reduces both the quality and quantity of life for patients. The pathophysiology of OA pain is complex and often difficult to explain solely by radiological structural changes. One reason for this discrepancy is pain sensitization (peripheral sensitization [PS] and central sensitization [CS]) in OA. Thus, an understanding of pain sensitization is important when considering treatment strategies and development for OA pain. In recent years, pro-inflammatory cytokines, nerve growth factors (NGFs), and serotonin have been identified as causative agents that induce peripheral and central sensitization and are becoming therapeutic targets for OA pain. However, the characteristics of the clinical manifestations of pain sensitization elicited by these molecules remain unclear, and it is not well understood who among OA patients should receive the therapeutic intervention. Thus, this review summarizes evidence on the pathophysiology of peripheral and central sensitization in OA pain and the clinical features and treatment options for this condition. While the majority of the literature supports the existence of pain sensitization in chronic OA pain, clinical identification and treatment of pain sensitization in OA are still in their infancy, and future studies with good methodological quality are needed.
| S-EPMC9949992 | biostudies-literature
Project description:BackgroundCentral sensitization (CS) is a condition characterized by a disproportionate response to pain stimuli, and is associated with chronic pain conditions such as fibromyalgia, but also with inflammatory arthropathies such as rheumatoid arthritis and psoriatic arthritis (PsA). CS has never been investigated in patients with psoriasis. The aim of this study is to investigate CS in patients with chronic plaque psoriasis.MethodsThis research involved a cross-sectional observational study of adult patients with moderate-to-severe psoriasis consecutively attending the outpatient clinic of the University Hospital of Verona. Demography, measures of disease severity or activity [i.e., Psoriasis Area and Severity Index (PASI), Disease Activity in Psoriatic Arthritis (DAPSA)], diagnosis of PsA, hypertension, and diabetes were collected. Central Sensitization Inventory (CSI), Dermatology Life Quality Index (DLQI), General Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) were administered.ResultsA total of 194 patients, including 115 (59%) men, with mean age of 54 ± 13 years, mean PASI of 12.7 ± 6.7, and mean DAPSA of 14.4 ± 3.8 were included. In total, 134 patients (79%) had only psoriasis while 60 (31%) had psoriasis and PsA; 19 (10%) patients had CSI score ≥ 40, which is the threshold for diagnosing CS. The proportion of CS ≥ 40 was higher in patients with PsA compared with psoriasis (17% versus 7%, p = 0.031). The mean CSI score in patients with PsA was higher compared with those with only psoriasis (27.5 ± 13.5 versus 20.7 ± 13.7, p = 0.002). An association between CSI and DLQI [β = 1.25 (95% CI 0.85-1.66)], PASI [β = 1.22 (95% CI 0.74-1.65)], GAD-7 [β = 2.07 (95% CI 1.69-2.45)] and PHQ-9 [β = 2.16 (95% CI 1.76-2.54)] was found independently from age, gender, diabetes, and PsA.ConclusionsCentral sensitization may be associated with psoriasis, particularly in those with high PASI, concomitant PsA, anxiety, depression, and severe quality of life impairment.
| S-EPMC10149419 | biostudies-literature
Project description:The IL-12 family members, IL-12, IL-23, IL-27 and IL-35, are heterodimeric cytokines that share subunits and have important roles in autoimmunity. As well as their structural relationship the IL-12 family cytokines share some biological characteristics but have functional differences. These cytokines contribute to immune-mediated inflammation and our improved knowledge of their actions has led to alteration of the T(H)1-T(H)2 paradigm. In rheumatoid arthritis (RA), leukocyte migration, bone erosions and angiogenesis are modulated by an IL-23-IL-17 cascade, which can be negated in part by IL-12, IL-27 and IL-35 function. However, the IL-12 family members are a relatively new area of research and data have been generated mostly at the preclinical stage. Further studies in patients with RA are, therefore, required to determine whether these cytokines are valid targets for RA therapy.
| S-EPMC10091854 | biostudies-literature
Project description:Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
| S-EPMC3268359 | biostudies-other
Project description:ObjectiveTo determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA).MethodsOne hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables.ResultsA good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]).ConclusionLow CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.
| S-EPMC8078061 | biostudies-literature
Project description:The aims of this study were to (1) examine the pattern of experimental pain responses in the affected and nonaffected extremities in patients with shoulder pain and (2) explore the intraindividual association between sensitization states derived from experimental pain testing.Experimental pain responses from 58 patients with shoulder pain (17 women, aged 18 to 52 y) were compared with those from 56 age-matched and sex-matched pain-free volunteers (16 women, aged 21 to 58 y). Experimental pain responses included pressure pain threshold (PPT), thermal pain threshold and tolerance, and suprathreshold heat pain response. Comparisons were made between the affected and nonaffected extremities of clinical participants and the average response of extremities in control participants. Peripheral and central sensitization indexes were computed for clinical participants using standardized scores and percentile cutoffs on the basis of the data from the control sample. Experimental pain responses in clinical participants observed beyond the 25th and 75th percentile of control sample responses were used for investigation of intraindividual association of sensitization states.PPT at the acromion and masseter on the affected side of clinical participants were diminished compared with that on their nonaffected side (P<0.015). Bilateral sensitivity in clinical participants was noted for PPT at the acromion and suprathreshold heat pain response (P<0.015). Peripheral and central sensitization indexes demonstrated that individuals with shoulder pain present with variable patterns of peripheral and central sensitization.Collectively, experimental pain responses supported peripheral and central sensitization in response to pressure and thermal stimuli. No clear association was made between individuals exhibiting peripheral or central sensitization, thus suggesting heterogeneity in pain processing in this clinical population.
| S-EPMC3732495 | biostudies-other
Project description:Central sensitization (CS) is regarded as an important contributing factor for chronification of musculoskeletal pain (MSP). It is crucial to identify CS, as targeted multimodal treatment may be indicated. The primary objective of this study was therefore to explore pain experience of individuals with MSP+CS in order to gain a better understanding of symptoms in relation to CS from a patient perspective. The secondary objective was to investigate whether pain experiences of patients with MSP+CS differ from those of individuals with neuropathic pain (NP).We conducted a comparative Group Delphi Study including patients with MSP+CS and neuropathic pain (NP). 13 guiding questions were used to gather information about sensory discriminatory, affective and associated bodily, mental and emotional phenomena related to the pain experience of patients. Descriptions were categorized using qualitative content analysis. Additionally, patients completed several pain related questionnaires.Nine participants with MSP+CS and nine participants with NP participated. The Delphi procedure revealed three main themes: psycho-emotional factors, bodily factors and environmental factors. Descriptions of patients with MSP+CS showed a complex picture, psycho-emotional factors seem to have a considerable impact on pain provocation, aggravation and relief. Impairments associated with mental ability and psyche affected many aspects of daily life. In contrast, descriptions of patients with NP revealed a rather mechanistic and bodily oriented pain experience.Patients with MSP+CS reported distinct features in relation to their pain that were not captured with current questionnaires. Insight in patient's pain experience may help to choose and develop appropriate diagnostic instruments.
| S-EPMC5552165 | biostudies-other