The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain

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.

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Tribbles and arthritis: what are the links?

Biochemical Society Transactions ◽

10.1042/bst20150076 ◽

2015 ◽

Vol 43 (5) ◽

pp. 1051-1056 ◽

Cited By ~ 2

Author(s):

Andrew D. Rowan ◽

Gary J. Litherland

Keyword(s):

Rheumatoid Arthritis ◽

Current Knowledge ◽

Cell Signalling ◽

Cartilage Destruction ◽

Signalling Pathways ◽

Signal Transduction Pathways ◽

Intracellular Protein ◽

Cellular Mechanisms ◽

Intracellular Protein Degradation ◽

The Impact

The pseudo-kinase family of tribbles (TRIB) proteins has been linked to a variety of cell signalling pathways and appears to have functionally divergent roles with respect to intracellular protein degradation and the ability to regulate signal transduction pathways. In the arthritides, inflammation and a wide variety of pro-inflammatory pathways have been implicated to drive the cartilage destruction and consequent disability associated with both rheumatoid arthritis (RA) and osteoarthritis (OA). Despite burgeoning evidence linking the TRIB to inflammation-related pathologies such as diabetes, multiple sclerosis and cancer, very little is known about their roles in arthritis. The present review discusses current knowledge of the impact of TRIB on pro-inflammatory cellular mechanisms and pathways known to be important in the pathogenesis of RA and OA.

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Gestational Diabetes Mellitus and Infant Adiposity at Birth: A Systematic Review and Meta-Analysis of Therapeutic Interventions

Journal of Clinical Medicine ◽

10.3390/jcm10040835 ◽

2021 ◽

Vol 10 (4) ◽

pp. 835

Author(s):

Manoja P. Herath ◽

Jeffrey M. Beckett ◽

Andrew P. Hills ◽

Nuala M. Byrne ◽

Kiran D. K. Ahuja

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fat Mass ◽

Metabolic Disorders ◽

Later Life ◽

Therapeutic Interventions ◽

Increased Risk ◽

The Impact

Exposure to untreated gestational diabetes mellitus (GDM) in utero increases the risk of obesity and type 2 diabetes in adulthood, and increased adiposity in GDM-exposed infants is suggested as a plausible mediator of this increased risk of later-life metabolic disorders. Evidence is equivocal regarding the impact of good glycaemic control in GDM mothers on infant adiposity at birth. We systematically reviewed studies reporting fat mass (FM), percent fat mass (%FM) and skinfold thicknesses (SFT) at birth in infants of mothers with GDM controlled with therapeutic interventions (IGDMtr). While treating GDM lowered FM in newborns compared to no treatment, there was no difference in FM and SFT according to the type of treatment (insulin, metformin, glyburide). IGDMtr had higher overall adiposity (mean difference, 95% confidence interval) measured with FM (68.46 g, 29.91 to 107.01) and %FM (1.98%, 0.54 to 3.42) but similar subcutaneous adiposity measured with SFT, compared to infants exposed to normal glucose tolerance (INGT). This suggests that IGDMtr may be characterised by excess fat accrual in internal adipose tissue. Given that intra-abdominal adiposity is a major risk factor for metabolic disorders, future studies should distinguish adipose tissue distribution of IGDMtr and INGT.

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O26 Non-serious infections in patients with RA: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Rheumatology ◽

10.1093/rheumatology/keaa110.025 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Katie Bechman ◽

Kapil Halai ◽

Sam Norton ◽

Andrew P Cope ◽

Kimme L Hyrich ◽

...

Keyword(s):

Quality Of Life ◽

Rheumatoid Arthritis ◽

British Society ◽

Tnf Inhibitor ◽

Drug Survival ◽

Increased Risk ◽

Serious Infections ◽

The Impact ◽

Biologics Register

Abstract Background Patients with rheumatoid arthritis (RA) are at an increased risk of infection. Most attention has been given to serious infections, but these are the tip of the iceberg. Non-serious infections (NSI) are far more frequent, and although not life-threatening, have potential to impact treatment outcomes (drug survival) and quality of life. Our objective was to describe frequency of NSI and compare incidence of NSI by biologic drug within the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. NSI was identified as not requiring hospitalisation, intravenous therapy or leading to disability or death. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered ‘at risk’ from the date of commencing biologic treatment for 3 years. Drug exposure was defined by agent; TNF inhibitor, IL-6 inhibitor, anti-CD20 or csDMARD only. To account for a high frequency of events, a multiple-failure Cox model was used. Multivariable adjustment included age, gender, DAS28-ESR, HAQ-DI, disease duration, smoking, steroid usage, year recruited to BSRBR-RA, line of biologic therapy and cumulative infection number. Results There were 17,304 NSI in 10,099 patients, with an event rate of 27.0 per year (95% CI 26.6 to 27.4). Increasing age, female gender, comorbidity burden, corticosteroid therapy, DAS28 and HAQ-DI were associated with an increased risk of NSI. The rate of NSI was numerically lowest with csDMARDs. Compared to TNFi, IL-6 inhibitor had a higher risk of NSI, whilst the csDMARD cohort had a lower risk. Between the TNFi agents, adalimumab had a higher risk than etanercept (Table 1). Conclusion These results confirm that NSI is a frequent occurrence for patients, which historically has received little attention in research literature. The data suggest biologics increase the risk of NSI, especially IL-6 inhibition. Whilst unmeasured confounding must be considered, the magnitude of effects are large and it seems likely that a causal link between targeted immunosuppression and NSI risk exists. Further research is needed to understand the impact of NSI on clinical outcomes including drug survival and quality of life. Disclosures K. Bechman: None. K. Halai: None. S. Norton: None. A.P. Cope: None. K.L. Hyrich: Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway: Honoraria; for speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

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Television Viewing and Cognitive Dysfunction of Korean Older Adults

Healthcare ◽

10.3390/healthcare8040547 ◽

2020 ◽

Vol 8 (4) ◽

pp. 547

Author(s):

Mi Sook Jung ◽

Eunyoung Chung

Keyword(s):

Older Adults ◽

Cognitive Dysfunction ◽

Cognitive Aging ◽

Significant Risk ◽

Multivariate Logistic Regression Analysis ◽

Later Life ◽

Significant Risk Factor ◽

Tv Viewing ◽

Increased Risk ◽

The Impact

This study examined the association between television (TV) viewing and cognitive dysfunction in elderly Koreans. Among participants of the 2014 National Survey of Older Koreans, 9644 were considered in this study. To better identify the association between two factors, propensity score (PS) matching with exact method was used. Finally, 168 viewers and non-viewers each were selected based on estimated PS on key variables and eliminating double matches. Multivariate logistic regression analysis was performed when controlling for possible covariates. Viewers were more likely to have cognitive dysfunction than non-viewers, with significant differences in most covariates. After correcting confounding effects of these covariates with PS matching, TV viewing was found to be a significant risk factor of cognitive dysfunction, along with absence of diagnosed hypertension and non-participation in physical leisure activities. TV viewing might be associated with increased risk of cognitive dysfunction in later life. Appropriate education and strategies to minimize TV viewing among older adults should be established to contribute to attenuating cognitive aging. More interventional studies can help older adults, caregivers, and healthcare professionals explore the cognitively beneficial alternatives to TV use considering the impact of socioeconomic factors of selecting TV viewing as a preferred leisure activity.

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Biological Activity of c-Peptide in Microvascular Complications of Type 1 Diabetes—Time for Translational Studies or Back to the Basics?

International Journal of Molecular Sciences ◽

10.3390/ijms21249723 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9723

Author(s):

Aleksandra Ryk ◽

Aleksandra Łosiewicz ◽

Arkadiusz Michalak ◽

Wojciech Fendler

Keyword(s):

Type 1 Diabetes ◽

Growth Factor ◽

Transforming Growth Factor ◽

Negative Impact ◽

Current Knowledge ◽

Microvascular Complications ◽

C Peptide ◽

Increased Risk ◽

The Impact

People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.

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Risk of diabetes mellitus associated with disease-modifying antirheumatic drugs and statins in rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-209954 ◽

2016 ◽

Vol 76 (5) ◽

pp. 848-854 ◽

Cited By ~ 31

Author(s):

Gulsen Ozen ◽

Sofia Pedro ◽

Marie E Holmqvist ◽

Michael Avery ◽

Frederick Wolfe ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Diabetes Mellitus ◽

Adult Population ◽

Data Bank ◽

Self Report ◽

Increased Risk ◽

Cox Proportional Hazard Models ◽

Synthetic Dmards ◽

Disease Modifying ◽

The Impact

ObjectiveTo investigate the rate of incident diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) and the impact of disease-modifying antirheumatic drug (DMARD) and statin treatments.MethodsWe studied patients with RA and ≥1 year participation in the National Data Bank for Rheumatic Diseases without baseline DM from 2000 through 2014. DM was determined by self-report or initiating DM medication. DMARDs were categorised into four mutually exclusive groups: (1) methotrexate monotherapy (reference); (2) any abatacept with or without synthetic DMARDs (3) any other DMARDs with methotrexate; (4) all other DMARDs without methotrexate; along with separate statin, glucocorticoid and hydroxychloroquine (yes/no) variables. Time-varying Cox proportional hazard models were used to adjust for age, sex, socioeconomic status, comorbidities, body mass index and RA severity measures.ResultsDuring a median (IQR) 4.6 (2.5–8.8) years of follow-up in 13 669 patients with RA, 1139 incident DM cases were observed. The standardised incidence ratio (95% CI) of DM in patients with RA (1.37, (1.29 to 1.45)) was increased compared with US adult population. Adjusted HR (95% CI) for DM were 0.67 (0.57 to 0.80) for hydroxychloroquine, 0.52 (0.31 to 0.89) for abatacept (compared with methotrexate monotherapy), 1.31 (1.15 to 1.49) for glucocorticoids and 1.56 (1.36 to 1.78) for statins. Other synthetic/biological DMARDs were not associated with any risk change. Concomitant use of glucocorticoids did not alter DM risk reduction with hydroxychloroquine (HR 0.69 (0.51 to 0.93)).ConclusionsIn RA, incidence of DM is increased. Hydroxychloroquine and abatacept were associated with decreased risk of DM, and glucocorticoids and statins with increased risk.

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Early growth and postprandial appetite regulatory hormone responses

British Journal Of Nutrition ◽

10.1017/s0007114513000950 ◽

2013 ◽

Vol 110 (9) ◽

pp. 1591-1600 ◽

Cited By ~ 10

Author(s):

Mia-Maria Perälä ◽

Eero Kajantie ◽

Liisa M. Valsta ◽

Jens J. Holst ◽

Jaana Leiviskä ◽

...

Keyword(s):

Test Meal ◽

Metabolic Diseases ◽

Hormone Secretion ◽

Later Life ◽

Early Growth ◽

Birth Cohort Study ◽

Slow Increase ◽

Increased Risk ◽

Hormone Responses ◽

The Impact

Strong epidemiological evidence suggests that slow prenatal or postnatal growth is associated with an increased risk of CVD and other metabolic diseases. However, little is known whether early growth affects postprandial metabolism and, especially, the appetite regulatory hormone system. Therefore, we investigated the impact of early growth on postprandial appetite regulatory hormone responses to two high-protein and two high-fat content meals. Healthy, 65–75-year-old volunteers from the Helsinki Birth Cohort Study were recruited; twelve with a slow increase in BMI during the first year of life (SGI group) and twelve controls. Subjects ate a test meal (whey meal, casein meal, SFA meal and PUFA meal) once in a random order. Plasma glucose, insulin, TAG, NEFA, ghrelin, peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and a satiety profile were measured in the fasting state and for 4 h after each test meal. Compared with the controls, the SGI group had about 1·5-fold higher insulin responses after the whey meal (P= 0·037), casein meal (P= 0·023) and PUFA meal (P= 0·002). TAG responses were 34–69 % higher for the SGI group, but only the PUFA-meal responses differed significantly between the groups. The PYY response of the SGI group was 44 % higher after the whey meal (P= 0·046) and 115 % higher after the casein meal (P= 0·025) compared with the controls. No other statistically significant differences were seen between the groups. In conclusion, early growth may have a role in programming appetite regulatory hormone secretion in later life. Slow early growth is also associated with higher postprandial insulin and TAG responses but not with incretin levels.

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Influence of innate immune activation on endocrine and metabolic pathways in infancy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00542.2020 ◽

2021 ◽

Author(s):

Karen M O'Connor ◽

Minoo Ashoori ◽

Maria L Dias ◽

Eugene Dempsey ◽

Ken D. O'Halloran ◽

...

Keyword(s):

Neonatal Sepsis ◽

Metabolic Pathways ◽

Current Knowledge ◽

Later Life ◽

Innate Immune ◽

Adjunctive Treatment ◽

Future Research ◽

Term Infants ◽

Immune System Activation ◽

Increased Risk

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

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Proinflammatory Role of Vascular Endothelial Growth Factor in the Pathogenesis of Rheumatoid Arthritis: Prospects for Therapeutic Intervention

Mediators of Inflammation ◽

10.1155/2008/129873 ◽

2008 ◽

Vol 2008 ◽

pp. 1-6 ◽

Cited By ~ 46

Author(s):

Seung-Ah Yoo ◽

Seung-Ki Kwok ◽

Wan-Uk Kim

Keyword(s):

Rheumatoid Arthritis ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Current Knowledge ◽

Chronic Inflammatory Disease ◽

Vascular Endothelial ◽

New Therapeutic Approaches ◽

Anti Vegf ◽

Endothelial Growth Factor

Recent experimental and clinical studies have placed new emphasis on the role of angiogenesis in chronic inflammatory disease. Vascular endothelial growth factor (VEGF) and its receptors are the best characterized system in the regulation of rheumatoid arthritis (RA) by angiogenesis. Furthermore, in addition to its angiogenic role, VEGF can act as a direct proinflammatory mediator during the pathogenesis of RA, and protect rheumatoid synoviocytes from apoptosis, which contributes to synovial hyperplasia. Therefore, the developments of synovial inflammation, hyperplasia, and angiogenesis in the joints of RA patients seem to be regulated by a common cue, namely, VEGF. Agents that target VEGF, such as anti-VEGF antibody and aptamer, have yielded promising clinical data in patients with cancer or macular degeneration, and in RA patients, pharmacologic modulations targeting VEGF or its receptor may offer new therapeutic approaches. In this review, the authors integrate current knowledge of VEGF signaling and information on VEGF antagonists gleaned experimentally and place emphasis on the use of synthetic anti-VEGF hexapeptide to prevent VEGF interacting with its receptor.

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Cancer and Aging: Two Tightly Interconnected Biological Processes

Cancers ◽

10.3390/cancers13061400 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1400

Author(s):

Lieze Berben ◽

Giuseppe Floris ◽

Hans Wildiers ◽

Sigrid Hatse

Keyword(s):

Older Patients ◽

Current Knowledge ◽

Geriatric Oncology ◽

Individual Treatment ◽

Treatment Regimens ◽

Patients With Cancer ◽

Increased Risk ◽

The Impact

Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general health and functional status amongst older persons, treatment of cancer is a major challenge in this vulnerable population. Older patients often experience more side effects of anticancer treatments. Over-treatment should be avoided to ensure an optimal quality of life. On the other hand, under-treatment due to fear of toxicity is a frequent problem and can lead to an increased risk of relapse and worse survival. There is a delicate balance between benefits of therapy and risk of toxicity. Robust biomarkers that reflect the body’s biological age may aid in outlining optimal individual treatment regimens for older patients with cancer. In particular, the impact of age on systemic immunity and the tumor immune infiltrate should be considered, given the expanding role of immunotherapy in cancer treatment. In this review, we summarize current knowledge concerning the mechanistic connections between aging and cancer, as well as aging biomarkers that could be helpful in the field of geriatric oncology.

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