Brain Neuroplasticity Related to Lateral Ankle Ligamentous Injuries: A Systematic Review.
Sports medicine (Auckland, N.Z.)
BACKGROUND:Lateral ankle sprains are the most common ankle injuries in sports and have the highest recurrence rates. Almost half of the patients experiencing lateral ankle sprains develop chronic ankle instability. Patients with chronic ankle instability experience persistent ankle dysfunctions and detrimental long-term sequelae. Changes at the brain level are put forward to explain these undesirable consequences and high recurrence rates partially. However, an overview of possible brain adaptations related to lateral ankle sprains and chronic ankle instability is currently lacking. OBJECTIVE:The primary purpose of this systematic review is to provide a comprehensive overview of the literature on structural and functional brain adaptations related to lateral ankle sprains and in patients with chronic ankle instability. METHODS:PubMed, Web of Science, Scopus, Embase, EBSCO-SPORTDiscus and Cochrane Central Register of Controlled Trials were systematically searched until 14 December, 2022. Meta-analyses, systematic reviews and narrative reviews were excluded. Included studies investigated functional or structural brain adaptations in patients who experienced a lateral ankle sprain or with chronic ankle instability and who were at least 18 years of age. Lateral ankle sprains and chronic ankle instability were defined following the recommendation of the International Ankle Consortium. Three authors independently extracted the data. They extracted the authors' name, publication year, study design, inclusion criteria, participant characteristics, the sample size of the intervention and control groups, methods of neuroplasticity testing, as well as all means and standard deviations of primary and secondary neuroplasticity outcomes from each study. Data reported on copers were considered as part of the control group. The quality assessment tool for observational and cross-sectional studies was used for the risk of bias assessment. This study is registered on PROSPERO, number CRD42021281956. RESULTS:Twenty articles were included, of which only one investigated individuals who experienced a lateral ankle sprain. In all studies combined, 356 patients with chronic ankle instability, 10 who experienced a lateral ankle sprain and 46 copers were included. White matter microstructure changes in the cerebellum have been related to lateral ankle sprains. Fifteen studies reported functional brain adaptations in patients with chronic ankle instability, and five articles found structural brain outcomes. Alterations in the sensorimotor network (precentral gyrus and supplementary motor area, postcentral gyrus and middle frontal gyrus) and dorsal anterior cingulate cortex were mainly found in patients with chronic ankle instability. DISCUSSION:The included studies demonstrated structural and functional brain adaptations related to lateral ankle sprains and chronic ankle instability compared to healthy individuals or copers. These adaptations correlate with clinical outcomes (e.g. patients' self-reported function and different clinical assessments) and might contribute to the persisting dysfunctions, increased re-injury risk and long-term sequelae seen in these patients. Thus, rehabilitation programmes should integrate sensorimotor and motor control strategies to cope with neuroplasticity related to ligamentous ankle injuries.
10.1007/s40279-023-01834-z
The brain-joint axis in osteoarthritis: nerves, circadian clocks and beyond.
Berenbaum Francis,Meng Qing-Jun
Nature reviews. Rheumatology
Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field.
10.1038/nrrheum.2016.93
[Concept and understanding of non-radiographic axial spondyloarthritis].
Zhonghua yi xue za zhi
Since the publication of the classification criteria for axial spondyloarthritis (axSpA) by Assessment of SpondyloArthritis international Society (ASAS), a new disease concept "non-radiographic axial spondyloarthritis (nr-axSpA)" has emerged. Some domestic experts in China have translated it as "radiologically negative" axSpA, but it can easily lead to misunderstandings literally, as not all patients with nr-axSpA are completely free from radiological abnormalities. This article briefly describes the evolution of the concept of axSpA, proposes to translate the term of nr-axSpA directly rather than "radiologically negative" axSpA, compares the differences and similarities between nr-axSpA and radiologically negative axSpA, delineates the relationship between nr-axSpA and early ankylosing spondylitis, and points out not all the patients who meet the ASAS classification criteria for nr-axSpA are genuine patients with axSpA, because of the relatively low specificity of the ASAS classification criteria. Five common scenarios easily leading to misdiagnosis of nr-axSpA are exampled to remind domestic colleagues.
10.3760/cma.j.cn112137-20230901-00363
Challenges in non-radiographic axial spondyloarthritis.
Joint bone spine
Non-radiographic axial spondyloarthritis (nr-axSpA) is part of the spectrum or continuum of axSpA and is characterized by the absence of definite structural damage in the sacroiliac joints. The introduction of the concept of axSpA with two - non-radiographic and radiographic - stages stimulated activities related to the improvement of early diagnosis and treatment of this disease, but also opened a number of controversial topics in the field. In this article, we are discussing several challenges related to the concept of nr-axSpA, the diagnosis, and the treatment in the historical context and in the light of the recent data.
10.1016/j.jbspin.2022.105468
Diagnosis, monitoring, and management of axial spondyloarthritis.
Rheumatology international
Axial spondyloarthritis (axSpA) is a chronic condition predominantly affecting the spine and sacroiliac joints. This article provides an in-depth overview of the current approaches to diagnosing, monitoring, and managing axSpA, including insights into developing terminology and diagnostic difficulties. A substantial portion of the debate focuses on the challenging diagnostic procedure, noting the difficulty of detecting axSpA early, particularly before the appearance of radiologic structural changes. Despite normal laboratory parameters, more than half of axSpA patients experience symptoms. X-ray and magnetic resonance imaging (MRI) are essential for evaluating structural damage and inflammation. MRI can be beneficial when there is no visible structural damage on X-ray as it can help unravel bone marrow edema (BME) as a sign of ongoing inflammation. The management covers both non-pharmacological and pharmacological approaches. Lifestyle modifications, physical activity, and patient education are essential components of the management. Pharmacological therapy, including nonsteroidal anti-inflammatory drugs (NSAIDs) and biologic disease-modifying anti-rheumatic drugs (bDMARDs), are explored, emphasizing individualized treatment. To effectively manage axSpA, a comprehensive and well-coordinated approach is necessary, emphasizing the significance of a multidisciplinary team. Telehealth applications play a growing role in axSpA management, notably in reducing diagnostic delays and facilitating remote monitoring. In conclusion, this article underlines diagnostic complexities and emphasizes the changing strategy of axSpA treatment. The nuanced understanding offered here is designed to guide clinicians, researchers, and healthcare providers toward a more comprehensive approach to axSpA diagnosis and care.
10.1007/s00296-024-05615-3
Sacroiliac radiographic progression over 10 years in axSpA: data from the DESIR inception cohort.
Annals of the rheumatic diseases
OBJECTIVES:To evaluate sacroiliac radiographic progression over a 10-year follow-up and determine the baseline factors associated with such progression in patients with recent-onset axial spondyloarthritis (axSpA, <3 years). METHODS:This analysis was performed in the DESIR cohort (NCT01648907). The radiographic status of the patients (radiographic axSpA (r-axSpA) vs non-radiographic axSpA (nr-axSpA)) was based on the modified New York (mNY) criteria. Information on mNY criteria on the pelvic radiographs was obtained in four reading waves over a 10-year period. Images were blinded and centrally read by 3 trained readers. The % of mNY net progressors (ie, number of 'progressors' minus number of 'regressors' divided by the total number of patients) was assessed in completers (ie, pelvic radiographs at baseline and 10 years). The yearly likelihood of mNY+ was estimated using an integrated analysis (ie, including all patients with at least one available mNY score ('intention-to-follow' population) using a generalised estimating equations model and time-varying tumour necrosis factor (TNF) use as a confounder. Baseline predictors of mNY+ during 10 years were evaluated. RESULTS:Completers included 294 patients, while intention-to-follow included 659 participants. In the completers, the net % progression (from nr-axSpA to r-axSpA) was 5.8%. In the intention-to-follow population, the probability of being mNY+ was estimated to increase 0.87% (95% CI 0.56 to 1.19) per year (ie, 8.7% after 10 years) while when introducing TNF inhibitors (TNFi) as a time-varying covariate, the probability was 0.45% (95% CI 0.09 to 0.81) (ie, 4.5% after 10 years). Baseline bone marrow oedema (BME) on MRI of the sacroiliac joints (SIJ) was associated with being mNY+ over time OR 6.2 (95% CI 5.3 to 7.2) and OR 3.1 (95% CI 2.4 to 3.9) in HLA-B27+ and HLA-B27-, respectively). Male sex, symptom duration >1.5 years, Axial Spondyloarthritis Disease Activity Score ≥2.1 and smoking (only in HLA-B27 positives) were also associated with being mNY+ over 10 years. BME was not found to be a mediator of the HLA-B27 effect on mNY+ at 10 years. CONCLUSIONS:The yearly likelihood of switching from nr-axSpA to r-axSpA in patients after 10 years of follow-up was low, and even lower when considering TNFi use.
10.1136/ard-2023-225184
Axial spondyloarthritis.
Sieper Joachim,Poddubnyy Denis
Lancet (London, England)
The term axial spondyloarthritis covers both patients with non-radiographic and radiographic axial spondyloarthritis, which is also termed ankylosing spondylitis. The disease usually starts in the third decade of life with a male to female ratio of two to one for radiographic axial spondyloarthritis and of one to one for non-radiographic axial spondyloarthritis. More than 90% heritabilty has been estimated, the highest genetic association being with HLA-B27. The pathogenic role of HLA-B27 is still not clear although various hypotheses are available. On the basis of evidence from trials the cytokines tumour necrosis factor (TNF)-α and interleukin-17 appear to have a relevant role in pathogenesis. The mechanisms of interaction between inflammation and new bone formation is still not completely understood but clarification will be important for the prevention of long-term structural damage of the bone. The development of new criteria for classification and for screening of patients with axial spondyloarthritis have been crucial for the early indentification and treatment of such patients, with MRI being the most important existing imaging method. Non-steroidal anti-inflammatory drugs and TNF blockers are effective therapies. Blockade of interleukin-17 is a new and relevant treatment option.
10.1016/S0140-6736(16)31591-4
Axial spondyloarthritis.
Navarro-Compán Victoria,Sepriano Alexandre,El-Zorkany Bassel,van der Heijde Désirée
Annals of the rheumatic diseases
Axial spondyloarthritis (axSpA) encompasses both radiographic and non-radiographic axSpA. It is a chronic inflammatory disease with a predilection for involving the axial skeleton. The most common presenting symptoms are chronic back pain and spinal stiffness but peripheral and extra-musculoskeletal manifestations occur also frequently. The diagnosis of axSpA relies on the recognition of a clinical pattern of the disease, based on clinical, laboratory and imaging features. The Assessment in SpondyloArthritis international Society classification criteria for axSpA are valid and well implemented for research purposes. Sustained disease activity, measured by validated tools such as the Ankylosing Spondylitis Disease Activity Score, leads to irreversible structural damage and poor functioning and therefore should be abrogated. As part of the management algorithm, non-steroidal anti-inflammatory drugs remain as the first line of pharmacological treatment besides physiotherapy. As a second line, tumour necrosis factor inhibitor and interleukin-17 inhibitor are available but recently Janus kinase inhibitors have also shown efficacy in improving symptoms of the disease.
10.1136/annrheumdis-2021-221035
Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.
Li Zhixiu,Wu Xin,Leo Paul J,De Guzman Erika,Akkoc Nurullah,Breban Maxime,Macfarlane Gary J,Mahmoudi Mahdi,Marzo-Ortega Helena,Anderson Lisa K,Wheeler Lawrie,Chou Chung-Tei,Harrison Andrew A,Stebbings Simon,Jones Gareth T,Bang So-Young,Wang Geng,Jamshidi Ahmadreza,Farhadi Elham,Song Jing,Lin Li,Li Mengmeng,Wei James Cheng-Chung,Martin Nicholas G,Wright Margaret J,Lee MinJae,Wang Yuqin,Zhan Jian,Zhang Jin-San,Wang Xiaobing,Jin Zi-Bing,Weisman Michael H,Gensler Lianne S,Ward Michael M,Rahbar Mohammad Hossein,Diekman Laura,Kim Tae-Hwan,Reveille John D,Wordsworth Bryan Paul,Xu Huji,Brown Matthew A,
Annals of the rheumatic diseases
OBJECTIVE:We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS:PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), and sacroiliac MRI. RESULTS:In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for these values were 51.9% and 97.9%, respectively. CONCLUSIONS:PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.
10.1136/annrheumdis-2020-219446
Assessment of intracranial vessels in association with carotid atherosclerosis and brain vascular lesions in rheumatoid arthritis.
Oláh Csaba,Kardos Zsófia,Sepsi Mariann,Sas Attila,Kostyál László,Bhattoa Harjit Pal,Hodosi Katalin,Kerekes György,Tamási László,Valikovics Attila,Bereczki Dániel,Szekanecz Zoltán
Arthritis research & therapy
BACKGROUND:Stroke has been associated with rheumatoid arthritis (RA). We assessed patients with RA and healthy control subjects by transcranial Doppler (TCD), carotid ultrasonography and brain magnetic resonance imaging (MRI). METHODS:Altogether, 41 female patients with RA undergoing methotrexate (MTX) or biologic treatment and 60 age-matched control subjects underwent TCD assessment of the middle cerebral artery (MCA) and basilar artery. Pulsatility index (PI), resistivity (resistance) index (RI) and circulatory reserve capacity (CRC) were determined at rest (r) and after apnoea (a) and hyperventilation (h). The presence of carotid plaques and carotid intima-media thickness (cIMT) were also determined. Intracerebral vascular lesions were investigated by brain MRI. RESULTS:MCA PI and RI values at rest and after apnoea were significantly increased in the total and MTX-treated RA populations vs control subjects. MCA CRC was also impaired, and basilar artery PI was higher in RA. More patients with RA had carotid plaques and increased cIMT. Linear regression analysis revealed that left PI(r) and RI(r) correlated with disease duration and that left PI(r), RI(r), PI(a), PI(h) and basilar PI correlated with disease activity. Right CRC inversely correlated with 28-joint Disease Activity Score. Disease activity was an independent determinant of left PI(a) and right CRC. Compared with long-term MTX treatment alone, the use of biologics in combination with MTX was associated with less impaired cerebral circulation. Impaired cerebral circulation was also associated with measures of carotid atherosclerosis. CONCLUSIONS:To our knowledge, this is the first study to show increased distal MCA and basilar artery occlusion in RA as determined by TCD. Patients with RA also had CRC defects. We also confirmed increased carotid plaque formation and increased cIMT. Biologics may beneficially influence some parameters in the intracranial vessels.
10.1186/s13075-017-1422-x
Exploring Cerebrovascular Function in Osteoarthritis: "Heads-up".
Physiological reports
Individuals with osteoarthritis (OA) are at greater risk of cardiovascular and cerebrovascular incidents; yet, cerebrovascular control remains uncharacterized. Our primary outcome was to acquire cerebrovascular control metrics in patients with OA and compare measures to healthy control adults (CTL) without OA or cardiovascular complications. Our primary covariate was a 10-year risk factor for cardiovascular and stroke incidents, and secondary covariates were other cardiovascular disease risk factors (i.e., body mass index, carotid intima media thickness, and brachial flow-mediated dilation). Our secondary outcomes were to assess anatomical and functional changes that may be related to cerebrovascular reactivity were also acquired such as white matter lesion volume and brief cognitive assessments. In 25 adults (n = 13 CTL, n = 12 OA), under hypercapnia, magnetic resonance imaging (3T) was used to acquire a "Global Cerebrovascular Reactivity" index across the larger intracranial cerebral arteries and white matter lesions, and transcranial Doppler was used for both middle cerebral artery hemodynamic responses to hypercapnia and to assess autoregulation via a sit-to-stand task. Compared to CTL, OA had lower "Global Cerebrovascular Reactivity" index responses to hypercapnia, autoregulatory responses, and greater white matter lesions (P < 0.05). These differences persisted after covarying for the outlined primary and secondary covariates. Patients with OA, in the absence of known cardiovascular disease, can exhibit pre-clinical and impaired (compared to CTL) peripheral and cerebrovascular control metrics.
10.14814/phy2.14212
Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success.
Sergeeva Marina,Rech Jürgen,Schett Georg,Hess Andreas
Arthritis research & therapy
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients' subjective feeling after the start of TNFα neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNFα blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI.
10.1186/s13075-015-0783-2
Reorganization of functional brain network architecture in chronic osteoarthritis pain.
Human brain mapping
Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by subdividing the KOA data into discovery and testing groups and tested the generalizability of our findings in HOA. Despite brain global topological properties being conserved in OA, we show there is a network wide pattern of reorganization that can be captured at the subject-level by a single measure, the hub disruption index. We localized reorganization patterns and uncovered a shift in the hierarchy of network hubs in OA: primary sensory and motor regions and parahippocampal gyrus behave as hubs and insular cortex loses its central placement. At an intermediate level of network structure, frontoparietal and cingulo-opercular modules showed preferential reorganization. We examined the association between network properties and clinical correlates: global disruption indices and isolated degree properties did not reflect clinical parameters; however, by modeling whole brain nodal degree properties, we identified a distributed set of regions that reliably predicted pain intensity in KOA and generalized to hip OA. Together, our findings reveal that while conserving global topological properties, brain network architecture reorganizes in OA, at both global and local scale. Network connectivity related to OA pain intensity is dissociated from the major hub disruptions, challenging the extent of dependence of OA pain on nociceptive signaling.
10.1002/hbm.25287
Pain in ankylosing spondylitis: a neuro-immune collaboration.
Bidad Katayoon,Gracey Eric,Hemington Kasey S,Mapplebeck Josiane C S,Davis Karen D,Inman Robert D
Nature reviews. Rheumatology
Clinicians have commonly differentiated chronic back pain into two broad subsets: namely, non-inflammatory (or mechanical) back pain and inflammatory back pain. As the terminology suggests, the latter category, in which ankylosing spondylitis (AS) is prominent, presupposes a close link between pain and inflammation. Advances in research into the genetics and immunology of AS have improved our understanding of the inflammatory processes involved in this disease, and have led to the development of potent anti-inflammatory biologic therapeutic agents. However, evidence from clinical trials and from biomarker and imaging studies in patients with AS indicate that pain and inflammation are not always correlated. Thus, the assumption that pain in AS is a reliable surrogate marker for inflammation might be an over-simplification. This Review provides an overview of current concepts relating to neuro-immune interactions in AS and summarizes research that reveals an increasingly complex interplay between the activation of the immune system and pain pathways in the nervous system. The different types of pain experienced by patients with AS, insights from brain imaging studies, neurological mechanisms of pain, sex bias in pain and how the immune system can modify pain in patients with AS are also discussed.
10.1038/nrrheum.2017.92
Chronic Pain Severity and Sociodemographics: An Evaluation of the Neurobiological Interface.
The journal of pain
Chronic pain is variably associated with brain structure. Phenotyping based on pain severity may address inconsistencies. Sociodemographic groups also differ in the experience of chronic pain severity. Whether differences by chronic pain severity and/or sociodemographic groups are indicated in pain-related areas of the brain is unknown. Relations between 2 measures of chronic pain severity and brain structure via T1-weighted MRI were investigated and sociodemographic group differences explored. The observational study included 142 community-dwelling (68 non-Hispanic Black [NHB] and 74 non-Hispanic White [NHW]) adults with/at risk for knee osteoarthritis. Relationships between chronic pain severity, sociodemographic groups, and a priori selected brain structures (postcentral gyrus, insula, medial orbitofrontal, anterior cingulate, rostral middle frontal gyrus, hippocampus, amygdala, thalamus) were explored. Chronic pain severity associated with cortical thickness. NHB participants reported lower sociodemographic protective factors and greater clinical pain compared to NHWs who reported higher sociodemographic protective factors and lower clinical pain. Greater chronic pain severity was associated with smaller amygdala volumes in the NHB group and larger amygdala volumes in the NHW group. Brain structure by chronic pain stage differed between and within sociodemographic groups. Overall, chronic pain severity and sociodemographic factors are associated with pain-related brain structures. Our findings highlight the importance of further investigating social and environmental contributions in the experience of chronic pain to unravel the complex array of factors contributing to disparities. PERSPECTIVE: The study presents data demonstrating structural brain relationships with clinical pain severity, characteristic pain intensity and chronic pain stage, differ by sociodemographic groups. Findings yield insights into potential sources of previous inconsistent pain-brain relationships and highlights the need for future investigations to address social and environmental factors in chronic pain disparities research.
10.1016/j.jpain.2021.07.010
Microbiota and chronic inflammatory arthritis: an interwoven link.
Journal of translational medicine
BACKGROUND:Only recently, the scientific community gained insights on the importance of the intestinal resident flora for the host's health and disease. Gut microbiota in fact plays a crucial role in modulating innate and acquired immune responses and thus interferes with the fragile balance inflammation versus tolerance. MAIN BODY:Correlations between gut bacteria composition and the severity of inflammation have been studied in inflammatory bowel diseases. More recently similar alterations in the gut microbiota have been reported in patients with spondyloarthritis, whereas in rheumatoid arthritis an accumulating body of evidence evokes a pathogenic role for the altered oral microbiota in disease development and course. In the context of dysbiosis it is also important to remember that different environmental factors like stress, smoke and dietary components can induce strong bacterial changes and consequent exposure of the intestinal epithelium to a variety of different metabolites, many of which have an unknown function. In this perspective, and in complex disorders like autoimmune diseases, not only the genetic makeup, sex and immunologic context of the individual but also the structure of his microbial community should be taken into account. CONCLUSIONS:Here we provide a review of the role of the microbiota in the onset, severity and progression of chronic inflammatory arthritis as well as its impact on the therapeutic management of these patients. Furthermore we point-out the complex interwoven link between gut-joint-brain and immune system by reviewing the most recent data on the literature on the importance of environmental factors such as diet, smoke and stress.
10.1186/s12967-016-0989-3
Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain.
Bone research
Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.
10.1038/s41413-024-00316-w
Brain Correlates of Continuous Pain in Rheumatoid Arthritis as Measured by Pulsed Arterial Spin Labeling.
Lee Yvonne C,Fine Alexander,Protsenko Ekaterina,Massarotti Elena,Edwards Robert R,Mawla Ishtiaq,Napadow Vitaly,Loggia Marco L
Arthritis care & research
OBJECTIVE:Central nervous system pathways involving pain modulation shape the pain experience in patients with chronic pain. The aims of this study were to understand the mechanisms underlying pain in patients with rheumatoid arthritis (RA) and to identify brain signals that may serve as imaging markers for developing targeted treatments for RA-related pain. METHODS:Patients with RA and matched control subjects underwent functional magnetic resonance imaging, using pulsed arterial spin labeling. The imaging conditions included 1) resting state, 2) low-intensity stimulus, and 3) high-intensity stimulus. Stimuli consisted of mechanical pressure applied to metacarpophalangeal (MCP) joints with an automated cuff inflator. The low-intensity stimulus was inflation to 30 mm Hg. The high-intensity stimulus was the amount of pressure required to achieve a pain intensity rating of 40 on a 100-point scale for each RA patient, with the same amount of pressure used in the matched control. RESULTS:Among RA patients, regional cerebral blood flow (rCBF) in the medial frontal cortex and dorsolateral prefrontal cortex increased during both low-pressure and high-pressure stimulation. No rCBF changes were observed in pain-free controls. Region-of-interest analyses in RA patients showed that baseline rCBF in the medial frontal cortex was negatively correlated with the pressure required for the high-intensity stimulus and positively correlated with pain induced by the low-intensity stimulus. Baseline rCBF was also marginally correlated with disease activity). Regional CBF during high pain was positively correlated with pain severity and pain interference. CONCLUSION:In response to clinically relevant joint pain evoked by pressure applied to the MCP joint, neural processing in the medial frontal cortex increases and is directly associated with clinical pain in patients with RA.
10.1002/acr.23601
Subcortical brain anatomy as a potential biomarker of persistent pain after total knee replacement in osteoarthritis.
Pain
ABSTRACT:The neural mechanisms for the persistence of pain after a technically successful arthroplasty in osteoarthritis (OA) remain minimally studied, and direct evidence of the brain as a predisposing factor for pain chronicity in this setting has not been investigated. We undertook this study as a first effort to identify presurgical brain and clinical markers of postarthroplasty pain in knee OA. Patients with knee OA (n = 81) awaiting total arthroplasty underwent clinical and psychological assessment and brain magnetic resonance imagining. Postoperative pain scores were measured at 6 months after surgery. Brain subcortical anatomic properties (volume and shape) and clinical indices were studied as determinants of postoperative pain. We show that presurgical subcortical volumes (bilateral amygdala, thalamus, and left hippocampus), together with shape deformations of the right anterior hippocampus and right amygdala, associate with pain persistence 6 months after surgery in OA. Longer pain duration, higher levels of presurgical anxiety, and the neuropathic character of pain were also prognostic of postsurgical pain outcome. Brain and clinical indices accounted for unique influences on postoperative pain. Our study demonstrates the presence of presurgical subcortical brain factors that relate to postsurgical persistence of OA pain. These preliminary results challenge the current dominant view that mechanisms of OA pain predominantly underlie local joint mechanisms, implying novel clinical management and treatment strategies.
10.1097/j.pain.0000000000002932
Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive-Behavioral Interventions for Rheumatoid Arthritis Fatigue: A Magnetic Resonance Imaging Brain Study.
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive-behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. METHODS:A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). RESULTS:Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ß = -0.46, SD 0.61; ß = -0.32, SD 0.47, respectively). CONCLUSION:The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.
10.1002/art.42755
Structural and functional brain changes in people with knee osteoarthritis: a scoping review.
PeerJ
Background:Knee osteoarthritis is a highly prevalent disease worldwide that leads to functional disability and chronic pain. It has been shown that not only changes are generated at the joint level in these individuals, but also neuroplastic changes are produced in different brain areas, especially in those areas related to pain perception, therefore, the objective of this research was to identify and compare the structural and functional brain changes in knee OA healthy subjects. Methodology:Searches in MEDLINE (PubMed), EMBASE, WOS, CINAHL, SCOPUS, Health Source, and Epistemonikos databases were conducted to explore the available evidence on the structural and functional brain changes occurring in people with knee OA. Data were recorded on study characteristics, participant characteristics, and brain assessment techniques. The methodological quality of the studies was analysed with Newcastle Ottawa Scale. Results:Sixteen studies met the inclusion criteria. A decrease volume of the gray matter in the insular region, parietal lobe, cingulate cortex, hippocampus, visual cortex, temporal lobe, prefrontal cortex, and basal ganglia was found in people with knee OA. However, the opposite occurred in the frontal lobe, nucleus accumbens, amygdala region and somatosensory cortex, where an increase in the gray matter volume was evidenced. Moreover, a decreased connectivity to the frontal lobe from the insula, cingulate cortex, parietal, and temporal areas, and an increase in connectivity from the insula to the prefrontal cortex, subcallosal area, and temporal lobe was shown. Conclusion:All these findings are suggestive of neuroplastic changes affecting the pain matrix in people with knee OA.
10.7717/peerj.16003
Neuropsychiatric manifestations in rheumatoid arthritis.
Joaquim Andrei F,Appenzeller Simone
Autoimmunity reviews
Rheumatoid arthritis (RA) is a chronic disease characterized by persistent synovitis, systemic inflammation, and the presence of autoantibodies. Neuropsychiatric manifestations are quite common in RA, including depression, cognitive dysfunction, behavior changes, spinal cord compression and peripheral nerve involvement. Potential causes include systemic inflammatory process, neural compression due to bone and joint destruction, side effects of medications and copying difficulties due to the chronicity of the disease. A high level of suspicious is required for an adequate diagnosis and treatment. In this review, we will discuss topographically the main neuropsychiatric manifestations described in RA patients, in an attempt to help in the management of these complex and multifaceted disease.
10.1016/j.autrev.2015.07.015
Brain predictors of fatigue in rheumatoid arthritis: A machine learning study.
PloS one
BACKGROUND:Fatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In this study, we identify brain differences between RA patients who improved and did not improve their levels of fatigue based on Chalder Fatigue Scale variation (ΔCFS≥ 2), and we compared the performance of different classifiers to distinguish between these samples at baseline. METHODS:Fifty-four fatigued RA patients underwent a magnetic resonance (MR) scan at baseline and 6 months later. At 6 months we identified those whose fatigue levels improved and those for whom it did not. More than 900 brain features across three data sets were assessed as potential predictors of fatigue improvement. These data sets included clinical, structural MRI (sMRI) and diffusion tensor imaging (DTI) data. A genetic algorithm was used for feature selection. Three classifiers were employed in the discrimination of improvers and non-improvers of fatigue: a Least Square Linear Discriminant (LSLD), a linear Support Vector Machine (SVM) and a SVM with Radial Basis Function kernel. RESULTS:The highest accuracy (67.9%) was achieved with the sMRI set, followed by the DTI set (63.8%), whereas classification performance using clinical features was at the chance level. The mean curvature of the left superior temporal sulcus was most strongly selected during the feature selection step, followed by the surface are of the right frontal pole and the surface area of the left banks of the superior temporal sulcus. CONCLUSIONS:The results presented evidence a superiority of brain metrics over clinical metrics in predicting fatigue changes. Further exploration of these methods may support clinicians to triage patients towards the most appropriate fatigue alleviating therapies.
10.1371/journal.pone.0269952
The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain.
Süß Patrick,Rothe Tobias,Hoffmann Alana,Schlachetzki Johannes C M,Winkler Jürgen
Frontiers in immunology
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.
10.3389/fimmu.2020.612104
Association of gout with brain reserve and vulnerability to neurodegenerative disease.
Nature communications
Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis.
10.1038/s41467-023-38602-6
Brain mapping inflammatory-arthritis-related fatigue in the pursuit of novel therapeutics.
The Lancet. Rheumatology
Despite developments in pharmacological treatments, chronic fatigue is an unresolved issue for most people with inflammatory arthritis that severely disrupts their personal and working lives. Fatigue in these patients is not strongly linked with peripheral disease activity but is associated with CNS-derived symptoms such as chronic pain, sleep disturbance, and depression. Therefore, a neurobiological basis should be considered when pursuing novel fatigue-specific therapeutics. In this Review, we focus on clinical imaging biomarkers that map candidate brain regions and are crucial in fatigue pathophysiology. We then evaluate neuromodulation techniques that could affect these candidate brain regions and are potential treatment strategies for fatigue in patients with inflammatory arthritis. We delineate work that is still required for neuroimaging and neuromodulation to eventually become part of a clinical pathway to treat and manage fatigue.
10.1016/S2665-9913(23)00007-3
Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial.
Annals of the rheumatic diseases
OBJECTIVES:To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS:Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS:A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib. CONCLUSION:Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib. TRIAL REGISTRATION NUMBER:NCT04169373.
10.1136/ard-2022-222608