leptin and Arthritis--Rheumatoid

White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculo-skeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA.

Topics: Adipokines; Arthritis, Rheumatoid; Humans; Immune System Diseases; Inflammation; Leptin; Osteoarthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by tumor-like hyperplasia and inflammation of the synovium, which causes synovial cell invasion into the bone and cartilage. In RA pathogenesis, various molecules in effector cells (i.e., immune cells and mesenchymal cells) are dysregulated by genetic and environmental factors. Consistent with the early stages of RA, these pathogenic cells cooperate and activate each other directly by cell-to-cell contact or indirectly

Topics: Arthritis, Rheumatoid; Cartilage; Humans; Inflammation; Leptin; Synovial Membrane

Leptin, an adipokine sharing structural characteristics of the long-chain helical cytokine family with the crucial role as a regulator in energy homeostasis, has been paid more and more attention to its immunoregulatory function. Emerging evidence has indicated the roles of leptin on autoimmune diseases such as systemic lupus erythematous (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA) and psoriasis, implying that leptin may be involved in autoimmune disorders. It is very definite that there exists immunocyte dysfunction in RA patients. Growing data has manifested that leptin is increased in both serum and synovial fluid of RA patients compared to healthy controls, suggesting leptin probably takes part in the pathogenesis of RA. The aim of this review is to discuss about what we currently know with regard to the role of leptin in immune system and its effects on RA crucial cells. To clarify the role of leptin in the pathogenesis of RA is beneficial to both the treatment and medical study.

Topics: Animals; Arthritis, Rheumatoid; Biomarkers; Disease Susceptibility; Gene Expression Regulation; Humans; Leptin; Lymphocytes; Macrophages

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.

Topics: Adipokines; Animals; Arthritis, Rheumatoid; Biomarkers; Disease Susceptibility; Gene Expression Regulation; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Resistin; Signal Transduction; T-Lymphocyte Subsets

The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis.. We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments. It is concluded that leptin may lead to OA via some signaling pathways. At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized.. Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person. In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase. Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients.. Treatment for leptin-increased obesity may be a treatment for OA. The role of leptin in OA cannot be ignored and needs to be further studied.

Topics: Arthritis, Rheumatoid; Chondrocytes; Humans; Leptin; Obesity; Osteoarthritis; Risk Factors; Signal Transduction; Synovial Fluid; Weight Loss

Rheumatoid arthritis affects millions of people worldwide and is considered a chronic multisystem disease whose causes are unknown. In general, the main objective of rheumatoid arthritis treatment is to improve the quality of life of patients by relieving pain, maintaining or improving functional capacity, preventing thus, disability. In recent years the role of adipokines in the pathogenesis of rheumatoid arthritis has been discussed but results are still conflicting. Although results from some studies have shown the implications of adipokines in the pathophysiology of autoimmune diseases, including rheumatoid arthritis, their role in the pathogenesis of disease progression is not clear. Thus, this review aimed to describe the association of key adipokines (leptin, resistin, visfatin and adiponectin) and rheumatoid arthritis, given the high prevalence of this disease and the important social impact caused by this chronic disabling disease.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Humans; Leptin; Nicotinamide Phosphoribosyltransferase; Resistin

Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.

Topics: Adipocytes; Appetite; Arthritis, Rheumatoid; Autoimmune Diseases; Disease Progression; Energy Metabolism; Hematopoietic Stem Cells; Humans; Hypothalamus; Leptin; Lupus Erythematosus, Systemic; Molecular Targeted Therapy; Receptors, Leptin; Signal Transduction; Weight Loss

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

Topics: Adaptive Immunity; Animals; Arthritis, Rheumatoid; Humans; Immune System Diseases; Immunity, Innate; Inflammation; Killer Cells, Natural; Leptin; Neutrophils; Osteoarthritis; Receptors, Leptin

This study aimed to evaluate the relationship between the circulating serum leptin level and rheumatoid arthritis (RA) and to establish a correlation between serum leptin levels and RA activity.. We searched the PUBMED, EMBASE, and Cochrane databases. A meta-analysis was performed, comparing the serum/plasma leptin levels in patients with RA and healthy controls. Correlation coefficients between serum leptin level and either disease activity score 28 (DAS28) or C‑reactive protein (CRP) in RA patients were also examined.. Thirteen studies with a total of 648 RA patients and 426 controls were included in this meta-analysis. Circulating leptin level was significantly higher in the RA group than in the control group (SMD = 1.056, 95 % CI = 0.647-1.465, p = 4.2 × 10. Our meta-analysis demonstrated that the circulating leptin level is significantly higher in patients with RA and that a small but significantly positive correlation exists between leptin levels and RA activity.

Topics: Arthritis, Rheumatoid; Biomarkers; Disease Progression; Humans; Leptin; Prevalence; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Statistics as Topic

Adipokines have been reported to be involved in the regulation of various physiological processes, including the immune response. Rheumatoid arthritis (RA) is an example of a systemic immune disease that causes chronic inflammation of the synovium and bone destruction in the joint. Recent therapeutic strategies based on the understanding of the role of cytokines and cellular mechanisms in RA have improved our understanding of angiogenesis. On the other hand, endogenous endothelial progenitor cells, which are a population isolated from peripheral blood monocytes have recently been identified as a homing target for pro-angiogeneic factor and vessel formation. In this review, we summarize the effects of common adipokines, such as adiponectin, leptin and resistin in RA pathogenesis and discuss other potential mechanisms of relevance for the therapeutic treatment of RA.

Topics: Adiponectin; Arthritis, Rheumatoid; Endothelial Cells; Humans; Leptin; MicroRNAs; Neovascularization, Pathologic; Resistin; Stem Cells

To determine the pathogenic role of adipokines, such as adiponectin and leptin, in rheumatoid arthritis (RA) by investigating whether serum levels of these adipokines correlated with disease activity in RA patients. Medline, Cochrane, EMBASE and Google Scholar were searched for studies published until 5 November 2015 reporting serum levels of leptin and adiponectin and measures of disease activity including DAS scores and radiographic progression scores (such as total change in SHS scores and number of erosions). Secondary outcomes included pain scores, functional status and health questionnaires. Only randomized controlled trials, cohort studies, or two-armed prospective or retrospective studies were included. A χ

Topics: Adiponectin; Adult; Arthritis, Rheumatoid; Biomarkers; Female; Humans; Leptin; Male; Middle Aged; Odds Ratio; Prognosis; Risk; Severity of Illness Index

The past 20 years of research on leptin has provided important insights into its role in rheumatoid arthritis (RA). Leptin is one of the different adipokines produced by the adipose tissue that influences the endocrine system, energy homeostasis and the immune response in several ways. Leptin is known to have predominantly pro-inflammatory effects, especially in the setting of chronic inflammation. Animal models of arthritis have illustrated well the participation of leptin in the inflammatory response within the joints. In patients with RA, numerous studies have evaluated the concentrations of leptin in the bloodstream and/or the joint cavity, showing higher levels compared to control populations. Leptin has also been found to correlate with clinical or biological measurements of disease activity of RA. Conversely, the relationship between serum leptin and joint structural damage is less evident. Leptin may also promote the development of atherosclerosis in RA and may contribute to the cardiovascular consequences of the metabolic syndrome that coexists with RA. Indeed, leptin could be a link between inflammation, metabolic risk factors and cardiovascular diseases in RA. Finally, due to abnormal body composition phenotypes with an increased prevalence of obesity in RA, the therapeutic response to traditional DMARDs and/or biological agents may be attenuated. This review discusses the multiple interplays that have been described between leptin and the clinical, radiographic and therapeutic aspects of RA.

Topics: Animals; Arthritis, Rheumatoid; Disease Models, Animal; Humans; Leptin

Inflammation is a complex mechanism of cell/tissue responses to injuries triggered by multiple causes, including trauma, pathogens or autoimmune abnormal responses. In the last years, a novel line of thought is emerging by giving a more holistic vision of chronic arthropathies through a recently identified group of molecules, called adipokines. Actually, most of these recently identified factors, produced prevalently by white adipose tissue but also by cells of the joints (chondrocytes and synovial fibroblasts) and immune cells, play a significant role in chronic inflammation. Adipokines dysregulation has emerged as a common characteristic of chronic inflammation in rheumatic diseases in particular when obesity or, more precisely, adipose tissue dysfunction is associated with common rheumatic diseases, such as osteoarthritis and rheumatoid arthritis. In this MiniReview, we discuss the role of adipokines in osteoarthritis and rheumatoid arthritis providing an updated overview of their pathophysiological role and potential use as therapeutic targets.

Topics: Adiponectin; Adipose Tissue, White; Animals; Arthritis, Rheumatoid; Humans; Inflammation; Leptin; Osteoarthritis

Published data regarding the association of leptin levels with rheumatoid arthritis (RA) are contradictory. To derive a more precise estimation of this relationship, a meta-analysis was performed.. Published literature from PubMed, Embase and Cochrane Library was obtained. Pooled standard mean difference (SMD) with 95 % confidence interval (CI) was calculated using fixed-effects or random-effect model analysis. Heterogeneity among studies was evaluated using the Cochran Q and I (2) statistics. The study quality was assessed by the Newcastle-Ottawa scale.. A total of 20 studies including 998 RA patients and 692 controls were finally included in the meta-analysis. Compared to healthy controls, RA patients had significantly higher leptin levels (SMD 1.19, 95 % CI 0.59-1.79). Subgroup analyses showed that region, race, age, body mass index (BMI), disease duration and disease activity were positively associated with plasma leptin levels in RA patients. Sensitivity analysis showed no significant change when any one study was excluded. Publication bias was also undetected.. The present meta-analysis suggested that leptin levels were higher in RA patients than those in healthy controls, which may be subject to different region, race, age, BMI, disease duration and disease activity.

Topics: Arthritis, Rheumatoid; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Humans; Leptin

Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity-like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Leptin; Receptors, Leptin; Signal Transduction

A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis.

Topics: Adipokines; Adiponectin; Animals; Arthritis, Rheumatoid; Humans; Leptin; Osteoarthritis; Rheumatic Diseases

To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings.. PubMed literature search complemented by review of bibliographies listed in identified articles.. Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adipokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented.. Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors.

Topics: Adipokines; Adiponectin; Animals; Arthritis, Rheumatoid; Connective Tissue; Disease Models, Animal; Humans; Leptin; Lupus Erythematosus, Systemic; Resistin

There is a growing evidence that both overnutrition and undernutrition negatively interfere with immune system. The overnutrition has been found to increase susceptibility to the development of inflammatory or autoimmune diseases. On the other hand, starvation or malnutrition has been more associated with increased susceptibility to infections. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role as an endocrine organ which produces number of active peptides, called adipokines. The adipokines, leptin and adiponectin represent a critical link among nutritional status, metabolism and immunity. Leptin is primarily known as a satiety factor regulating body weight by suppression of appetite and stimulation of energy expenditure, and its serum levels and gene expression in adipocytes strongly correlate with proportion of body fat stores. On the other hand, leptin is a pro-inflammatory adipokine inducing T helper 1 cells and may contribute to the development and progression of autoimmune responses. Adiponectin plays an important role as an insulin-sensitizing adipokine which production is decreased in obesity and in conditions associated with insulin resistance. Adiponectin also acts as an anti-inflammatory factor especially with regard to atherosclerosis, but in some chronic inflammatory/autoimmune diseases adiponectin may have pro-inflammatory effects and its production correlates with inflammatory markers and disease activity. This review discusses the main biological activities of leptin and adiponectin as well as their contribution to inflammatory and autoimmune processes with particular focus on rheumatoid arthritis and its experimental models.

Topics: Adiponectin; Adipose Tissue; Animals; Arthritis, Rheumatoid; Autoimmunity; Energy Metabolism; Humans; Inflammation; Leptin; Nutritional Physiological Phenomena

Topics: Adiponectin; Adipose Tissue; Arthritis, Rheumatoid; Cytokines; Humans; Leptin; Models, Immunological; Nicotinamide Phosphoribosyltransferase; Resistin

Both overnutrition and undernutrition affect energy metabolism, with overnutrition raising energy expenditure and undernutrition lowering it. Fever is a powerful stimulator of thermogenesis. In diseases such as cancer, AIDS, diabetes mellitus, and rheumatoid arthritis, whether energy expenditure is increased or decreased often depends on how advanced the disorder is. Early on, when the greater protein turnover characteristic of these conditions is paramount, energy expenditure is increased. In addition, in diseases such as cancer, AIDS, and rheumatoid arthritis in which cytokines are released, the cytokines' thermogenic effect initially increases the metabolic rate. However, as the disease becomes more advanced and leads to cachexia, energy expenditure drops below normal. Acute conditions such as burns and trauma significantly raise energy expenditure, primarily by increasing sympathetic response and the release of catecholamines, which are powerful stimulators of energy expenditure.

Topics: Acquired Immunodeficiency Syndrome; Adult; Age Factors; Aged; Arthritis, Rheumatoid; Basal Metabolism; Burns; Diabetes Mellitus; Eating; Energy Metabolism; Female; Humans; Leptin; Male; Middle Aged; Neoplasms; Obesity; Wounds and Injuries

To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients.. We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28)  ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000-1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05.. The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; -0.51 [95% CI -1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 -2.0 [95% CI -7.00, 3.1], P = 0.46 between groups).. Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients.. ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.

Topics: Adiponectin; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Diet, Reducing; Humans; Leptin; Obesity; Severity of Illness Index; Single-Blind Method; Synovitis

To comparatively investigate the differential effect of second-line tumour necrosis factor inhibitors (TNFis) versus other biological agents on cardiovascular disease (CVD) risk-associated biomarkers in patients with rheumatoid arthritis (RA).. We evaluated the serum levels of lipoprotein-associated apoproteins ApoA1 and ApoB100 and lipoprotein(a) (Lp(a)) and the leptin/adiponectin ratio (LAR) as an insulin resistance proxy in patients with RA from the Rotation Or Change (ROC) trial treated with either a second-line TNFi or another biologic (tocilizumab (TCZ), rituximab or abatacept) at baseline and week 24. We compared the changes in biomarker levels in each group and according to the EULAR response.. Of the 300 patients enrolled in the ROC trial, 203 were included in the study, including 96 in the second-line TNFi group and 107 in the other biological group. The measured biomarkers did not deteriorate between baseline and week 24 regardless of the group. A greater improvement in the LAR was noted in the other biological group (median (IQR) -0.12 ng/µg (-0.58 to 0.31) vs 0.04 (-0.19 to 0.43), p=0.033), and a greater improvement in the Lp(a) level was observed following treatment with TCZ than with a TNFi (-0.05 g/L (-0.11 to -0.01) vs -0.01 g/L (-0.02 to 0.01), p<0.001). When considering the patients' responses to treatment, improved biomarkers were mainly observed in the EULAR responders in each treatment group.. TNFis and non-TNFis were neutral on improved CVD risk-associated biomarkers in patients with RA insufficiently controlled by TNFis. TCZ could be associated with a better improvement concerning Lp(a) and LAR than TNFis. This improvement could be related to a good therapeutic response, thereby supporting the need of good control of RA.. ClinicalTrials.gov Identifier NCT01000441, registered on 22 October 2009.

Topics: Abatacept; Adiponectin; Aged; Antibodies, Monoclonal, Humanized; Apolipoprotein A-I; Apolipoprotein B-100; Arthritis, Rheumatoid; Biological Factors; Biomarkers; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Leptin; Lipoprotein(a); Male; Middle Aged; Risk Factors; Rituximab; Tumor Necrosis Factor Inhibitors

To investigate baseline levels of 12 serum biomarkers that constitute a multibiomarker disease activity test, as predictors of response to methotrexate (MTX) in patients with early rheumatoid arthritis (eRA).. In 298 patients from the Swedish Pharmacotherapy (SWEFOT) clinical trial, baseline serum levels of 12 proteins were analyzed for association with disease activity based on the 28-joint count Disease Activity Score (DAS28) after 3 months of MTX monotherapy using uni-/multivariate logistic regression. Primary outcome was low disease activity (LDA; DAS28 ≤ 3.2).. Of 298 patients, 104 achieved LDA after 3 months on MTX. Four of the 12 biomarkers [C-reactive protein (CRP), leptin, tumor necrosis factor receptor I (TNF-RI), and vascular cell adhesion molecule 1 (VCAM-1)] significantly predicted LDA based on stepwise logistic regression analysis. Dichotomization of patients using receiver-operating characteristic curve analysis-based cutoffs for these biomarkers showed significantly higher proportions with LDA among patients with lower versus higher levels of CRP or leptin (40% vs 23%, p = 0.004, and 40% vs 25%, p = 0.011, respectively), as well as among those with higher versus lower levels of TNF-RI or VCAM-1 (43% vs 27%, p = 0.004, and 41% vs 25%, p = 0.004, respectively). Combined score based on these biomarkers, adjusted for known predictors of LDA (smoking, sex, and age), associated with decreased chance of LDA (adjusted OR 0.45, 95% CI 0.32-0.62).. Low baseline levels of CRP and leptin, and high baseline levels of TNF-RI and VCAM-1 were associated with LDA after 3 months of MTX therapy in patients with eRA. Combination of these 4 biomarkers increased accuracy of prediction. [Trial registration number: NCT00764725].

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Female; Humans; Leptin; Male; Methotrexate; Middle Aged; Receptors, Tumor Necrosis Factor, Type I; Remission Induction; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA.. Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders.. Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26).. In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP.. WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Topics: Adipokines; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Chitinase-3-Like Protein 1; Disease Progression; Drug Therapy, Combination; Epidermal Growth Factor; Female; Foot Joints; Hand Joints; Humans; Hydroxychloroquine; Infliximab; Interleukin-6; Lectins; Leptin; Logistic Models; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Methotrexate; Multivariate Analysis; Prognosis; Radiography; Receptors, Tumor Necrosis Factor, Type I; Resistin; Serum Amyloid A Protein; Severity of Illness Index; Sulfasalazine; Treatment Outcome; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Rheumatoid arthritis (RA) is a chronic inflammatory disease that damages the synovial joints, and patients with it are often anorexic and cachectic with high morbidity and mortality. Biological therapy with anti-tumor necrosis factor (TNF)-α has been proven effective as a treatment for RA. However, the long-term effects of anti-TNF-α therapy on body weight, appetite, plasma gut hormones and leptin have not been investigated.. Twenty RA patients received subcutaneous injections of etanercept, a chimeric protein of human IgG1 Fc and TNF receptor p75, twice weekly for 12 consecutive months. Sequential changes in body weight, body fat, appetite rating, lipid profiles, gut hormones and leptin were measured at baseline and at 3 and 12 months after treatment. Ten RA patients who received non-biological disease modifying anti-rheumatic drugs were enrolled as the controls and were appraised at baseline and at 12 months after treatment (a nonrandomized study).. Significant weight gain, hyperuricemia, decreased fasting plasma glucose-dependent insulinotropic polypeptide (GIP) levels, and loss of post-oral glucose suppression of plasma leptin concentration were found in the patients after the 12-month course of etanercept therapy, but not in the controls. A transient decrease in fasting plasma acyl ghrelin occurred at 3 months during etanercept treatment. Appetite score and serum lipid profiles did not change in either group.. Long-term therapy with anti-TNF-α is promising in ameliorating body mass decrease in patients with active RA. Plasma levels of ghrelin, GIP and leptin may play significant roles in maintaining energy homeostasis in the anti-inflammatory responses during RA remission.

Topics: Adult; Antirheumatic Agents; Appetite; Arthritis, Rheumatoid; Body Composition; Body Mass Index; Cachexia; Etanercept; Female; Gastrointestinal Hormones; Humans; Immunoglobulin G; Leptin; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Weight Gain

Rheumatoid arthritis (RA) is associated with changes in body composition and bone mineral density (BMD). The purpose of the present study was to evaluate whether anti-TNF treatment in early RA has an impact on body composition and BMD besides that which could be achieved by intensive disease-modifying anti-rheumatic drug (DMARD) combination therapy.. Forty patients with early RA who failed treatment with methotrexate up to 20 mg/week for 3 months were randomised to addition of sulphasalazine and hydroxychloroquine (treatment A) or addition of infliximab (treatment B). At 3, 12 and 24 months, body composition and BMD were assessed by total-body dual-energy X-ray absorptiometry. At the same time points, leptin, adiponectin, apolipoproteins, insulin-like growth factor-1 (IGF-1) and markers of bone remodelling were analysed. Compliance to treatment was considered in the analyses. Data were analysed with a mixed, linear model.. Patients treated with anti-TNF had a significant increase in fat mass at 2 years, 3.8 (1.6 to 5.9) kg, in contrast to patients in treatment A, 0.4 (-1.5 to 2.2) kg (P = 0.040), despite similar reduction in disease activity. Both treatment strategies prevented loss of muscle mass and bone. Leptin concentrations increased significantly in both groups at 2 years and adiponectin increased significantly at 2 years in treatment A and at 1 year in treatment B. There were no significant changes in apolipoproteins or IGF-1. The markers of bone resorption decreased at 12 months in both treatment groups with no significant difference between the treatment groups.. Infliximab therapy increased body fat mass, an effect that was not achieved with the combination of DMARDs, despite a similar reduction in disease activity, and thus seemed to be drug specific. The increase of fat mass was not associated with an exacerbated atherogenic lipid profile. Leptin and adiponectin concentrations increased in both treatment groups. The increase of adiponectin may partially explain the reduced frequency of cardiovascular diseases found when disease activity is reduced in RA.. ISRCTN39045408.

Topics: Absorptiometry, Photon; Adiponectin; Adipose Tissue; Adult; Aged; Antibodies, Monoclonal; Antirheumatic Agents; Apolipoproteins; Arthritis, Rheumatoid; Body Composition; Bone Density; Bone Remodeling; Female; Humans; Hydroxychloroquine; Infliximab; Insulin-Like Growth Factor I; Leptin; Male; Methotrexate; Middle Aged; Radioimmunoassay; Sulfasalazine

Patients with rheumatoid arthritis (RA) appear to have increased plasma levels of leptin and adiponectin. These adipokines may be implicated in the pathophysiology of RA. Tumour necrosis factor alpha (TNF-alpha) is a potential modulator of adipokines. The effects of long-term anti-TNF treatment on plasma levels of leptin and adiponectin are not clear. The aim of this study was to assess the effects of 6-month anti-TNF treatment (infliximab) on leptin and adiponectin plasma levels in RA patients. Thirty women with RA were included in the study. Patients with diabetes mellitus, any endocrine disorder or receiving any hypolipidemic or antidiabetic medication were not included. Thirty healthy age- and body mass index-matched women served as controls. Plasma levels of leptin and adiponectin were measured with enzyme immunoassay methods prior to and after the 6-month treatment with infliximab. Mean age and disease duration of patients were 51.8 +/- 14.4 and 12.2 +/- 6.7 years, respectively. Body weight did not change significantly over the 6-month period. Plasma levels of leptin and adiponectin were higher in patients than controls and did not change significantly after 6-month treatment. Interestingly, in the tertile of patients with the highest baseline adiponectin concentrations, adiponectin levels were significantly reduced (P < 0.05). Infliximab treatment did not change plasma levels of leptin and adiponectin after 6-month treatment in the whole study population. However, a reduction of adiponectin levels was observed in patients with higher baseline adiponectin levels.

Topics: Adiponectin; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infliximab; Leptin; Middle Aged; Treatment Outcome; Tumor Necrosis Factor-alpha

Leptin regulates food intake and modulates immunity and inflammation. A positive feedback mechanism has been described between tumour necrosis factor (TNF) and leptin, and it has been suggested that leptin potentiates inflammation in patients with rheumatoid arthritis (RA).. To assess whether inflammation correlates with leptin concentrations in patients with RA, and whether anti-TNF treatment modulates leptin concentrations in these patients.. Leptin, IL6 and CRP were measured (at baseline and after 2 weeks of treatment) in the blood of 31 patients with RA starting either anti-TNF treatment or placebo, and in 18 healthy controls.. In patients with RA, plasma leptin concentrations at baseline correlated inversely with the degree of inflammation as assessed by C reactive protein (CRP; r(s)(2) = 0.21, p<0.01) or interleukin (IL) 6 concentrations (r(s)(2) = 0.22, p<0.008). Mean (SD) leptin concentrations did not differ between patients with RA and controls (6.0 (4.6) v 4.2 (2.8) ng/ml in men; 15.1 (7.9) v 13.4 (5.2) ng/ml in women). Short course anti-TNF treatment for 2 weeks did not modify leptin concentrations, despite significant reduction of CRP and IL6.. A significant inverse correlation between inflammation and leptin concentrations was found in patients with active RA, although plasma leptin concentrations did not significantly differ from those in healthy controls. This suggests that active chronic inflammation may lower plasma leptin concentrations. Two weeks' treatment with anti-TNF did not change plasma leptin concentrations and longer treatment may be needed to see an effect on leptin.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Double-Blind Method; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Leptin; Male; Middle Aged; Tumor Necrosis Factor-alpha

We determined associations between adipokines and abnormal body composition in patients with rheumatoid arthritis (RA).. Combining data from three RA cohorts, whole-body dual-energy absorptiometry measures of appendicular lean mass and fat mass indices were converted to age-, sex-, and race- and ethnicity-specific Z scores. Lean mass relative to fat mass was determined based on prior methods. Independent associations between body composition profiles and circulating levels of adiponectin, leptin, and fibroblast growth factor (FGF)-21 were assessed using linear and logistic regression models adjusting for demographic characteristics and study cohort. We also determined the improvement in the area under the curve (AUC) for prediction of low lean mass when adipokines were added to predictive models that included clinical factors such as demographic characteristics, study, and body mass index (BMI).. Among 419 participants, older age was associated with higher levels of all adipokines, whereas higher C-reactive protein level was associated with lower adiponectin levels and higher FGF-21 levels. Greater fat mass was strongly associated with lower adiponectin levels and higher leptin and FGF-21 levels. Higher levels of adiponectin, leptin, and FGF-21 were independently associated with low lean mass. The addition of adiponectin and leptin levels to regression models improved prediction of low lean mass when combined with demographic characteristics, study, and BMI (AUC 0.75 vs. 0.66).. Adipokines are associated with both excess adiposity and low lean mass in patients with RA. Improvements in the prediction of body composition abnormalities suggest that laboratory screening could help identify patients with altered body composition who may be at greater risk of adverse outcomes.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Body Composition; Body Mass Index; Humans; Leptin

To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA).. Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted.. Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P = 0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P = 0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P = 0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P = 0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients.. Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Cardiovascular Diseases; Coronary Artery Disease; Humans; Leptin; Risk Factors

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation and destruction.. Establish the association between Porphyromonas gingivalis (. The cross-sectional study evaluated 124 FDR and 124 healthy controls (HC). The clinical examination included joint and radiographic evaluation and calculation of BMI. Serum adipokine levels were measured (leptin, vaspin, adiponectin, resistin, and adipsin), as were the erythrocyte sedimentation rate, C-reactive protein, and anti-citrullinated protein antibodies. Investigations were performed to detect. In FDR, serum adipokine levels were associated with overweight and the presence of

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Complement Factor D; Cross-Sectional Studies; Humans; Leptin; Periodontal Diseases; Resistin

Adiponectin, leptin, and resistin are thought to be involved in the pathogenesis of rheumatoid arthritis (RA). However, the causal relationship between these adipokines and the risk for RA is unclear. We performed a range of two-sample Mendelian randomisation (MR) analyses to assess the causal effect of circulating adiponectin, leptin, and resistin on RA risk in European and East Asian individuals. Different sets of adiponectin-, leptin-, and resistin-related genetic variants were used as instruments for genetically determined adipokine levels. As body mass index (BMI) is a risk factor for RA and affects adipokine levels, multivariable MR was used to calculate the causal effect of each adipokine on RA risk taking BMI into account. Several MR analyses revealed no evidence of a causal relationship between circulating adiponectin, leptin, or resistin levels and RA risk in either Europeans or East Asians. Similarly, multivariable MR did not provide evidence of any causal effect of adiponectin, leptin, or resistin on RA risk when taking BMI into account. This MR study shows for the first time that genetically determined levels of adiponectin, leptin, or resistin do not have a direct causal effect on the risk of developing RA after adjustment for BMI.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Humans; Leptin; Resistin

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease in adults that is associated with significant joint issues and systemic inflammation. One of the signs of bone damage in RA is osteoporosis (OP). Leptin is an inflammatory protein that has been reported to be related to RA. The potential relationships among leptin, disease activity, and OP in Chinese patients with RA are not well known.. In total, 245 patients with RA and 120 healthy controls were included in this study. Detailed data on the clinical characteristics and laboratory features were collected. Information about physical activity and functional status was recorded using specific questionnaires. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The MECALL castor-50-hf model X-ray scanner was used for the two-hand (including wrist) photographs.. Serum leptin levels differed significantly between the RA group and healthy control subjects (1.27/3.29 vs. 0.17/0.24, Z=13.29, P<0.001). The positive rate of leptin protein in RA patients was 86.35%, which was higher than that in controls (19.55%) (χ. These results suggest that the level of serum leptin is associated with disease activity and secondary OP among Chinese patients with RA. Key Points • Serum leptin levels in RA patients are higher than those in normal control group. • Leptin was associated with disease activity. • Leptin was associated with the occurrence of systemic osteoporosis and affects bone erosion in RA patients.

Topics: Absorptiometry, Photon; Adult; Arthritis, Rheumatoid; Bone Density; East Asian People; Humans; Leptin; Osteoporosis

To analyse the role of body mass index (BMI) in the clinical response to biologic dis-ease-modifying anti-rheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). To per-form an in-depth analysis of the pathophysiology of obesity by assessing serum adipokine levels and their potential changes according to treatment.. This study involved 105 patients with RA starting tumour necrosis factor inhibitors (TNFi) or tocilizumab (TCZ). Patients were classified ac-cording to BMI as normal-weight and overweight/obesity. The clinical response to treatment was as-sessed by Clinical Disease Activity Index (CDAI) 6 months after initiation of bDMARDs. Serum adi-pokines (leptin and adiponectin) were determined using a commercial immunoassay kit in samples ob-tained before initiation of bDMARDs and after 6 months of treatment.. A correlation was observed between BMI and disease activity and between BMI and serum adipokines. Sixty percent of patients achieved low disease activity (LDA)/remission: 45 patients in TNFi group (64.2%) and 18 (51.4%) in TCZ group. In TNFi group, patients who did not attain LDA/remission had a higher BMI (kg/m2) ([28.7±5.1] vs. [24.5±4.6], p=0.001) and baseline CDAI (26.3 [17.4-33.9] vs. 19.8 [14.0-28.8], p<0.03). However, no differences in BMI or baseline CDAI were observed between patients who achieved LDA after 6 months in TCZ group.. Obesity influences the extent of LDA/remission in patients treated with TNFi, but not in patients treated with TCZ, probably because of underlying pathophysiological mechanisms intrinsic to the production of proinflammatory adi-pokines. Therefore, therapeutic strategies with a mechanism of action other than TNF inhibition would be more suitable for obese patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Biological Therapy; Body Mass Index; Cytokines; Humans; Leptin; Obesity; Treatment Outcome; Tumor Necrosis Factor Inhibitors

This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA.. Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality.. A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality.. Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Topics: Adipokines; Adiponectin; Adult; Arthritis, Rheumatoid; Cytokines; Female; Humans; Inflammation; Leptin; Male

Exercise has an anti-inflammatory effect and reduces fat mass. Leptin has been known to be proinflammatory adipokines mainly produced by adipocytes. However, few studies have investigated the association between exercise and changes in serum leptin levels of patients with RA. This study evaluated the effect of an individualized resistance exercise on inflammatory markers including leptin as well as muscle strength and exercise capacity in patients with rheumatoid arthritis (RA).. A total of 42 age- and sex-matched participants were assigned to a resistance exercise program (60 min, once a week for 12 weeks, and self-exercise twice a week) or to a control group. Muscle strength, exercise capacities, and inflammatory markers such as cytokines and adipokines were assessed at baseline and at 12 weeks follow-up. Longitudinal changes in muscle strength, exercise capacity, cytokines, and adipokines between groups were tested with repeated measures analysis of variance or using the generalized estimating equation, with adjustment for baseline disease activity score 28-C response protein as a covariate.. A total of 37 of 42 female patients with RA completed this prospective intervention study. Grip strength improved significantly in the exercise group (P < 0.05), while no between-group changes were found. Quadriceps contraction power (P for group-time interaction = 0.035 for the right side and P for group-time interaction = 0.012 for the left side) and 6-minute walking distance (P for group-time interaction = 0.021) were all improved significantly in the exercise group compared with the control group. In addition, serum leptin levels were significantly decreased in the exercise group compared with the control group (P for group-time interaction = 5.22 × 10. In addition to muscle strength and exercise capacity, the 12 weeks of individualized resistance exercise reduced serum leptin levels in keeping with body fat mass or visceral fat area, suggesting that serum leptin levels might be a surrogate marker of exercise in RA.

Topics: Arthritis, Rheumatoid; Female; Humans; Leptin; Longitudinal Studies; Prospective Studies; Resistance Training

To determine if adipocytokines are independently associated with the achievement of low disease activity (LDA) over long-term follow-up in a large rheumatoid arthritis (RA) registry.. This cohort study evaluated adults with RA from the Veteran's Affairs RA Registry. Adipocytokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum from enrollment. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox proportional hazard models evaluated associations between adipocytokines and rates of 1) DAS28 LDA and remission, 2) individual Boolean remission criteria and 3) initiation of a new bDMARD or tsDMARD.. There were 1,276 participants with a DAS28 >3.2 at enrollment. Of these, 827 achieved LDA and 598 achieved remission over 2,287 and 4,096 person-years, respectively. Patients in the highest quartile of adiponectin had lower rates LDA before and after adjustment [aHR Q4: 0.68 (0.53,0.87) p<0.001]. Those in the highest quartile of leptin and FGF-21 also had lower rates of LDA. Higher quartiles of adipocytokines were also associated with lower rates of achieving a low patient/evaluator global scores and low tender joint counts. Among 1,236 biologic-naïve participants, values above the median for adiponectin [HR: 1.67 (1.23,1.26) p = 0.001] and FGF-21 [HR: 1.27 (1.09,1.47) p = 0.002] were associated with a greater likelihood of initiating a b/tsDMARD.. Adipocytokines may serve as prognostic biomarkers of a more severe RA disease course. Additional study is needed to determine whether adipocytokines are phenotypic markers or whether they actively promote disease progression.

Topics: Adipokines; Adiponectin; Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Cohort Studies; Humans; Leptin; Remission Induction; Treatment Outcome

Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.

Topics: Adipokines; Adiponectin; Apolipoproteins A; Apolipoproteins B; Arthritis, Rheumatoid; Aryldialkylphosphatase; Biomarkers; Carotid Intima-Media Thickness; Complement Factor D; Follow-Up Studies; Humans; Janus Kinase Inhibitors; Janus Kinases; Leptin; Lipids; Peroxidase; Resistin; Thrombospondin 1; Tumor Necrosis Factor-alpha

Hypoxia is associated with the pathogenesis of rheumatoid arthritis (RA). RA fibroblast-like synoviocytes (FLSs) are able to differentiate into osteoblasts and adipocytes. In this study, we aimed to investigate the role of hypoxia in the osteogenesis or adipogenesis of RA-FLSs. Bioinformatics analysis was performed to profile gene expression in the datasets of GSE21959, GSE32006, and GSE55875, and flow cytometry was performed for FLS characterization, while Alizarin Redand Oil Red O staining for osteogenic or adipogenic differentiation of FLSs, respectively. RNA interference leptin knockdown was used to determine the role of leptin in the osteogenesis and adipogenesis of RA-FLSs, and the expression of osteogenic and adipogenic markers was quantified by RT-qPCR and Western blotting. FLSs exhibited a mesenchymal stem cell (MSC)-like phenotype and we observed a limited self-renewal capacity in RA-FLSs compared to that in MSCs, but it was still greater than osteoarthritis (OA)-FLSs. Hypoxia did not change the RA-FLS MSC-like phenotype but inhibited the osteogenic differentiation and promoted the adipogenic differentiation of RA-FLSs. From the bioinformatics analysis ofGSE21959, GSE32006, and GSE55875 datasets, we found leptin, the only perturbed hypoxia-mediated upregulated gene across the three profiled datasets. Leptin knockdown in RA-FLSs reversed the hypoxia-mediated reduction of osteogenesis and hypoxia-mediated enhancement of adipogenesis by elevated expression of osteogenic markers and reduced expression of adipogenic markers, respectively. Therefore, hypoxia-leptin regulation of the osteogenic and adipogenic differentiation of RA-FLSs advances our understanding of RA pathogenesis, meanwhile also provides opportunities for future therapeutic intervention of RA.

Topics: Adipogenesis; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Fibroblasts; Humans; Hypoxia; Leptin; Osteogenesis; Synoviocytes; Up-Regulation

The differential diagnosis of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) is difficult because of the lack of diagnostic clinical signs and reliable biomarkers. This study investigated microRNAs (miRNA) and adipokines as potential additional markers to discriminate PsA from RA. The expression profile of miRNA (miR-21, miR-140, miR-146a, miR-155, miR-181b, miR-223, miR-let-7e) and inflammatory cytokines (IL-1β, IL-6, IL-17a, IL-23a, TNF-α) from peripheral blood mononuclear cells of PsA and RA patients compared to healthy controls (HC) were evaluated by real-time PCR, and serum adipokines (adiponectin, chemerin, leptin, resistin, visfatin) and cytokines by ELISA assay. Univariable binary logistic regression was used to find the association between PsA and potential predictors. The gene expression of miRNA and cytokines and the serum levels of adipokines were found significantly different in PsA and RA patients compared to HC, as well as in PsA versus RA. MiR-140 gene expression resulted up-regulated in PsA patients and reduced in RA in comparison to HC, and, for the first time, significantly higher in PsA compared with RA. Serum levels of IL-23a and leptin were significantly increased in PsA and RA populations than in HC, as well as in PsA versus RA. Furthermore, circulating TNF-α was up-regulated in PsA and RA in comparison to controls, while resulted higher in RA than in PsA. Univariable binary logistic regression analysis found the above-mentioned markers associated to PsA versus RA. Our results first demonstrated an increased expression of circulating miR-140 and serum leptin in PsA patients compared to RA, which were identified as potential additional biomarkers to discriminate PsA from RA. Since the differential diagnosis of PsA and RA poses challenges in clinical practice, our data may help to enhance the diagnostic performance of PsA in daily practice.

Topics: Adipokines; Adult; Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Biomarkers; Case-Control Studies; Cytokines; Diagnosis, Differential; Female; Humans; Leptin; Male; MicroRNAs; Middle Aged

To investigate metabolic syndrome (MetS), disease activity, and adipokine levels among patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA) at the time of diagnosis and after 1 year of follow-up.. Patients with inflammatory joint diseases participating in the Northern Savo 2010 population-based longitudinal epidemiological study were evaluated for components of MetS (by National Cholesterol Education Program's Adult Treatment Panel III) and clinical parameters of disease activity. The adipokines adiponectin, adipsin, resistin, and leptin were measured at baseline and after 1 year of treatment with disease-modifying antirheumatic drugs.. Among 176 patients, MetS was detected in 42% of RA, 36% of SpA, and 51% of UA patients. Metabolic syndrome was associated with higher disease activity as measured by patient global assessment in RA and UA patients and increased pain in RA patients. Leptin levels were increased in patients with MetS, showing a linearly increasing trend with the number of components of MetS in SpA and UA, but not in RA. In RA patients, decrease in disease activity correlated with decrease in leptin levels. Resistin did not associate with MetS, but a decrease in resistin correlated with decrease in disease activity in RA and UA. In SpA, increased adiponectin level correlated with relief in disease activity, but not with MetS.. Metabolic syndrome was common in patients with newly diagnosed arthritides and associated with higher disease activity and increased leptin levels. Resistin responded to treatment of arthritis in RA and UA, leptin in RA, and adiponectin in SpA.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Humans; Leptin; Metabolic Syndrome

Cardiovascular diseases (CVDs) are important complications for patients with rheumatoid arthritis (RA). The study aimed to explore whether serum leptin is associated with a increased risk of cardiovascular (CV) events in patients with RA.. Two hundred twenty-three patients with RA were followed for a mean of 40 (range = 8-42) months. Serum leptin levels were measured at baseline. Cox regression analysis was performed to assess the association between leptin levels and the risk of CV events.. The univariate analysis showed that patients with RA with higher serum leptin levels had higher rates of CV events and CV mortality, respectively (P <.001). The logistic regression model showed that leptin was independently related to CVD history (odds ratio = 1.603, 95% confidence interval [CI], 1.329-2.195; P =.005) after adjusting for confounding factors in patients with RA at baseline. The multivariate Cox proportional hazard model suggested that leptin was an independent prognostic factor for CV events in patients with RA after adjustments were made for clinical confounding factors (hazard ratio = 2.467, 95% CI, 2.019-4.495; P <.001). The Kaplan-Meier analysis showed that compared with patients with RA with leptin levels below the median value (≤15.4 mg/L), patients with leptin above the median value (>15.4 μg/L) had a higher rate of CV events (P <.001).. Leptin was significantly associated with CV events in patients with RA. Elevated serum leptin levels may be a reliable prognostic factor for predicting CV complications in patients with RA.

Topics: Aged; Arthritis, Rheumatoid; Cardiovascular Diseases; Female; Humans; Leptin; Male; Middle Aged; Proportional Hazards Models

Adiponectin, leptin, and resistin are adipocytokines whose levels are elevated in blood and synovial fluid from patients with rheumatoid arthritis (RA). However, their role in RA pathogenesis is unclear. Here, we examined whether adipocytokines are associated with circulating chemokines, markers of inflammation and RA disease activity in patients with untreated newly diagnosed RA. Plasma levels of 15 chemokines, adiponectin, leptin, and resistin were measured using flow cytometry bead-based immunoassay or enzyme-linked immunosorbent assay (ELISA) in a cohort of 70 patients with untreated newly diagnosed RA. Markers of inflammation and disease activity were also assessed in all patients. Positive association was found between total adiponectin and CXCL10 (β = 0.344,

Topics: Adipokines; Adiponectin; Adult; Arthritis, Rheumatoid; Chemokines; Cohort Studies; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Resistin; Tretinoin

Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA).. In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24-72 weeks).. No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, -0.2 kg;. Weight and the leptin-adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients.

Topics: Adiponectin; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Body Weight; Drug Therapy, Combination; Female; Heart Disease Risk Factors; Humans; Leptin; Male; Methotrexate; Middle Aged; Receptors, Interleukin-6; Resistin; Retrospective Studies; Tumor Necrosis Factor-alpha

Leptin and adiponectin are produced mainly in adipocytes and classified as adipocytokines because of their possible involvement in inflammation and immunity. The aim of this study was to elucidate the relationships of these adipocytokines with the disease activities of RA. We examined leptin and adiponectin concentrations and inflammatory markers such as metalloproteinase-3 (MMP-3) in 136 patients with rheumatoid arthritis (RA) (26 males and 110 females, 69.6 ± 9.3 years) and 78 controls (36 males and 42 females, 66.7 ± 15.0 years). Serum leptin and adiponectin concentrations correlated positively (r = 0.565, P < 0.001) and negatively (r = -0.331, P < 0.001) to the amount of body fat, respectively. Serum leptin and adiponectin concentrations normalized by body fat mass were significantly higher in RA than those in controls [leptin, 1.24 (median) ng/mL/kg fat in RA vs. 0.76 ng/mL/kg fat in controls; adiponectin, 0.74 μg/mL/kg fat in RA vs. 0.44 μg/mL/kg fat in controls]. Normalized adiponectin concentrations correlated positively not only to the degree of bone destruction in Steinbrocker classification but also to serum MMP-3 concentrations. Normalized leptin concentrations did not correlate to the degree of bone destruction. We conclude that adiponectin but not leptin may be involved in joint damage in RA.

Topics: Adiponectin; Aged; Arthritis, Rheumatoid; Biomarkers; Body Mass Index; Case-Control Studies; Evaluation Studies as Topic; Female; Humans; Leptin; Male; Matrix Metalloproteinase 3; Reference Standards

Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) disease. Adiponectin is involved in the metabolism of glucose and lipids with favourable effects on CV disease, especially its high molecular weight (HMW) isoform. Body composition changes are described in RA with various phenotypes including obesity. The effects of tocilizumab on serum adiponectin and body composition, especially fat mass, in patients with RA are not well determined.. Patients with active RA despite previous csDMARDs and/or bDMARDs and who were tocilizumab naïve were enrolled in a multicentre open-label study. They were evaluated at baseline, 1, 3, 6 and 12 months. Clinical assessment included body mass index (BMI) and anthropometric measurements. Lipid and metabolic parameters, serum adiponectin (total and HMW), leptin, resistin and ghrelin were measured at each time point. Body composition (lean mass, fat mass, % fat, fat in the android and gynoid regions) was evaluated at baseline, 6 and 12 months.. One hundred seven patients were included. Both total and HMW adiponectin significantly increased from baseline to month 3, peaking respectively at month 3 (p = 0.0105) and month 1 (p < 0.0001), then declining progressively until month 6 to 12 and returning to baseline values. Significant elevation in HMW adiponectin persisted at month 6 (p = 0.001). BMI and waist circumference significantly increased at month 6 and 12, as well as lean mass at month 6 (p = 0.0097). Fat mass, percentage fat and android fat did not change over the study period. Lipid parameters (total cholesterol and LDL cholesterol) increased while glycaemia, insulin and HOMA-IR remained stable. Serum leptin, resistin and ghrelin did not change during follow-up.. Tocilizumab treatment in RA patients was associated with a significant increase in total and HMW adiponectin, especially at the onset of the treatment. Tocilizumab also induced a significant gain in lean mass, while fat mass did not change. These variations in adiponectin levels during tocilizumab treatment could have positive effects on the CV risk of RA patients. In addition, tocilizumab may have an anabolic impact on lean mass/skeletal muscle.. The ADIPRAT study was a phase IV open-label multicentre study retrospectively registered on ClinicalTrials.gov under the number NCT02843789 (date of registration: July 26, 2016).

Topics: Adiponectin; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Body Mass Index; Humans; Insulin Resistance; Leptin; Molecular Weight

Recently, increasing studies have revealed that leptin is involved in the development of rheumatoid arthritis (RA). This study is aimed at exploring the association of. We recruited 600 RA patients and 600 healthy controls from a Chinese population and analyzed their three. No significant difference in either allele or genotype frequencies of these three SNPs between RA patients and healthy controls was observed (all

Topics: Adult; Aged; Arthritis, Rheumatoid; Asian People; Case-Control Studies; China; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Male; Middle Aged; Models, Genetic; Polymorphism, Single Nucleotide

The aim: Was to evaluate the effect of 6-month pathogenetic treatment in combination with atorvastatinum on the endothelium function, lipid and adipokine levels, paroxonase activity and activity of inflammatory process in RA patients.. Materials and methods: The study included 55 patients with RA, dividing into two groups depending on the intended therapy. The first group included 33 patients with "traditional" treatment by methotrexate, glucocorticoids, and non-steroid anti-inflammatory drugs. The second group included 22 patients with "traditional" treatment and additionally prescribed of atorvastatinum 20 mg/day. The lipid profile, leptin, adipokine, paroxonase activity. C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) levels, FMDBA and IMT of carotid artery were determined in all participants of the study. Control parameters were recorded before the start, after 1 and 6 months of treatment.. Results: The FMDBA has increased by 32% in the second group, compared by only 10.9% in the first group. The dynamics of IMT in the first group was also twice lower than in group with the additional use of atorvastatinum. The leptin levels in the second group significantly decreased by 27% and adiponectin levels increased by 12.8%, than in the first group - by 12.8% and by 7% respectively. The appointment of statins over 6 months resulted in DAS28, TNF-α, ESR and CRP reduction by 15%, 31%, 25% and 21.5% respectively. In the first group the dynamics of indicate rates ranged from 7.8% to 22.5%, and was significantly lower than in the second group.. Conclusions: As a result of the study, it was found that the appointment of atorvastatinum 20 mg/day during 6 months not only reduces dyslipidemia, but also significantly reduces the inflammatory process and adipokine dysregulation, normalizes serum paraoxonase activity and improves the endothelium function.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Humans; Leptin; Methotrexate; Tumor Necrosis Factor-alpha

Topics: Arthritis, Rheumatoid; Body Mass Index; Case-Control Studies; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Overweight; Severity of Illness Index; Tumor Necrosis Factor-alpha

To develop and evaluate an adjusted score for the multi-biomarker disease activity (MBDA) test to account for the effects of age, sex and adiposity in patients with RA.. Two models were developed to adjust MBDA score for age, sex and adiposity, using either serum leptin concentration or BMI as proxies for adiposity. Two cohorts were studied. A cohort of 325 781 RA patients who had undergone commercial MBDA testing and had data for age, sex and serum leptin concentration was used for both models. A cohort of 1411 patients from five studies/registries with BMI data was used only for the BMI-adjusted MBDA score. Univariate and multivariate linear regression analyses evaluated the adjusted MBDA scores and conventional clinical measures as predictors of radiographic progression, assessed in terms of modified total Sharp score (ΔmTSS).. Two models were developed, based on findings that MBDA score was higher in females than males and increased with age, leptin concentration and BMI. In pairwise regression analyses, the leptin-adjusted (P = 0.00066) and BMI-adjusted (P = 0.0027) MBDA scores were significant independent predictors of ΔmTSS after adjusting for DAS28-CRP, whereas DAS28-CRP was not, after adjusting for leptin-adjusted (P = 0.74) or BMI-adjusted (P = 0.87) MBDA score. Moreover, the leptin-adjusted MBDA score was a significant predictor of ΔmTSS after adjusting for the BMI-adjusted MBDA score (P = 0.025) or the original MBDA score (0.027), whereas the opposite was not true.. Leptin-adjusted MBDA score significantly adds information to DAS28-CRP and the original MBDA score in predicting radiographic progression. It may offer improved clinical utility for personalized management of RA.

Topics: Adiposity; Adult; Age Factors; Aged; Arthritis, Rheumatoid; Biomarkers; Body Mass Index; Cohort Studies; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Predictive Value of Tests; Radiography; Reproducibility of Results; Severity of Illness Index; Sex Factors

Pro-inflammatory cytokines such as leptin and IL-6 play an important role in the development of cardiovascular risk. Determine the relationship between leptin and IL-6 concentrations with cardiovascular risk in patients with rheumatoid arthritis. We determined IL-6 and leptin levels in 77 patients with the diagnosis of rheumatoid arthritis. The cardiovascular risk was calculated using the modified Framingham scale. Statistical analysis was performed using SPSS 22 considering a significant p < 0.05. Serum leptin concentrations and cardiovascular risk (CVR) factors were compared and found that there was a significant difference between higher leptin values and disease activity (p 0.047), obesity (p 0.038), positive rheumatoid factor (p 0.009), tobacco (p 0.009), and metabolic syndrome (p 0.001). Likewise, a significant relationship was found between lower leptin concentrations and hydroxychloroquine consumption (p = 0.023). We found significant difference between IL-6 concentrations and disease activity (p 0.028), hypertriglyceridemia (p 0.023), LDL-C (p 0.029), and smoking (0.005). Similarly, an association between hydroxychloroquine consumption and low concentrations of IL-6 was found (p 0.005). Framingham CVR was calculated and the result obtained was multiplied by 1.5. The 35.2% of the population studied had a low Framingham CVR, 38.9% moderate, and 25.9% presented a high risk. We compared the level of CVR and serum leptin and IL-6 concentrations, finding that the highest CVR was the leptin and IL-6 values. There is a positive association between CVR and serum leptin concentrations. It is also significantly associated with traditional and non-traditional risk factors.

Topics: Adult; Arthritis, Rheumatoid; Biomarkers; Cardiovascular Diseases; Female; Humans; Interleukin-6; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Risk Factors

Multiple studies have found a direct relationship between leptin concentrations and disease activity in rheumatoid arthritis.. We studied 77 patients with the diagnosis of rheumatoid arthritis; the leptin determination was through an enzyme immunoassay. Disease activity was assessed by the DAS-28 CRP. A multivariate logistic regression model was used to determine the association between significant variables and leptin concentrations.. 40.3% of the patients were in remission, 41.6% were mildly active, 11.7% were moderately active and 6.5% were severely active. The results show an independent association between higher concentrations of leptin and disease activity (OR 1.7; 95% CI 1.4-3.2; p .03), the number of swollen joints (OR 4.6; 95% CI 1.7-8.3; p .000), the number of painful joints (OR 3.4; 95% CI 1.6-4.6; p .000), and the presence of metabolic syndrome (OR 1.3; 95% IC 1.2-1,9; p .045).. The data suggest that serum leptin is elevated in patients with active RA.

Topics: Adult; Anthropometry; Arthritis, Rheumatoid; C-Reactive Protein; Female; Humans; Immunoenzyme Techniques; Interleukin-6; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Severity of Illness Index

The determination of excess of body fat mass provides a more suitable determinant of obesity in rheumatoid arthritis patients; however, body mass index (BMI) may not be accurate for the quantification of adiposity. To identify a marker of excess adiposity in women with rheumatoid arthritis (RA) using different methods for fat mass evaluation. A cross-sectional study was conducted in adult female patients with RA. Disease activity was assessed by DAS28-ESR, and obesity was determined by waist circumference (WC), BMI and dual-energy X-ray absorptiometry (DXA). The Human Bone Metabolism kit (Merck Millipore, Darmstadt, Alemanha) was used to determine the plasma levels of leptin, TNF-α, IL-6, and IL-1β by quantification of serum proteins by technical microspheres (LUMINEX, TX, USA). Adiponectin was measured by enzyme-linked immunosorbent assay sandwich kit (R&D Systems, Minneapolis, MN, USA). Eighty-nine female patients, median age of 55.4 (± 11.6) years, and median disease duration of 16.4 (± 14.9) years were included. The frequency of obesity was 33.7% according to BMI, 89.9% with WC, and 56.1% with DXA. The median serum leptin concentration was the only marker that correlated with body fat percentage according to the three methods. This correlation was positive and not influenced by DAS28, C-reactive protein, erythrocyte sedimentation rate, or inflammatory cytokines levels (IL-6, TNF-α, IL-1β). Analysis of ROC curves determined the cut-off point of 10.3 ng/mL of leptin as an obesity marker, with a sensitivity of 96.43% and a specificity of 23.81%. Serum leptin correlates positively with fat mass and is potentially useful in excess fat mass determination in clinical practice.

Topics: Adult; Aged; Arthritis, Rheumatoid; Body Mass Index; Cross-Sectional Studies; Female; Humans; Leptin; Middle Aged; Obesity

Dyslipidemia has been reported to attribute to early death due to increased atherosclerosis leading to CVDs in patients with RA. Recent reports have suggested a role of adipocytokines in mediating joint damage rheumatoid arthritis (RA). RA has long been associated with increased cardiovascular risk as atherosclerosis is more prevalent in patients of RA than in the general population. Specific alleles of APOE gene have been reported to be associated with risk for atherosclerosis and LEP gene alleles have been associated with increased BMI. We evaluated the association of polymorphisms in the APOE and the LEP gene, with risk for developing RA and severity of joint damage in patients with RA.. Peripheral blood samples from age and ethnicity matched healthy controls and RA patients, recruited for the study, were collected and used for DNA isolation and allele typing for D7S1875 (LEP gene) and APOE using PCR-LP/RFLP based method reported in literature4,5 followed by data analysis using Medcalc.. Based on the findings of this study no correlation was seen between RA and LEP gene (D7S1875) allele/genotypes. It was seen that the APOE*4 allele was more prevalent in controls than in cases indicating that this allele is probably playing a significant protective role (p=0.0002, OR=0.3336, CI:0.1856-0.5997) as opposed to the other two Apo E alleles. The Apo E*3 allele was the most prevalent allele in both cases and controls which is similar to earlier reports from several different groups. No significant association was observed between the APOE genotype and the DAS28 score. Finally, it can be concluded that while the short allele of the D7S1875 (LEP gene) marker increases the risk for developing RA (OR=1.72, p=0.038) the APOE*4 allele seems to play a protective role in RA (OR=0.3336, p=0.0002).

Topics: Adult; Alleles; Apolipoprotein E4; Arthritis, Rheumatoid; Case-Control Studies; Female; Genetic Markers; Humans; Leptin; Male; Middle Aged; Prospective Studies; Severity of Illness Index

To investigate whether the Multi-Biomarker Disease Activity (MBDA) score predicts optimal add-on treatment in patients with early rheumatoid arthritis (RA) who were inadequate responders to MTX (MTX-IRs).. We analyzed data from 157 MTX-IRs (with a Disease Activity Score using the erythrocyte sedimentation rate [DAS28-ESR] >3.2) from the Swedish Pharmacotherapy (SWEFOT) trial who were randomized to receive triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) versus MTX plus infliximab. The MBDA score as a predictor of the subsequent DAS28-based response to each second-line treatment was analyzed at randomization with the Breslow-Day test for 2 × 2 groups, using both validated categories (low [<30], moderate [30-44], and high [>44]) and dichotomized categories (lower [≤38] versus higher [>38]).. Among the 157 patients, 12% had a low MBDA score, 32% moderate, and 56% high. Of those with a low MBDA score, 88% responded to subsequent triple therapy, and 18% responded to MTX plus infliximab (P = 0.006); for those with a high MBDA score, the response rates were 35% and 58%, respectively (P = 0.040). When using 38 as a cutoff for the MBDA score (29% patients with lower scores versus 71% with higher scores), the differential associations with response to triple therapy versus MTX plus infliximab were 79% versus 44% and 36% versus 58%, respectively (P = 0.001). Clinical and inflammatory markers had poorer predictive capacity for response to triple therapy or MTX plus infliximab.. In patients with RA who had an inadequate response to MTX, the MBDA score categories were differentially associated with response to subsequent therapies. Thus, patients with post-MTX biochemical improvements (lower MBDA scores) were more likely to respond to triple therapy than to MTX plus infliximab. If confirmed, these results may help to improve treatment in RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; C-Reactive Protein; Chitinase-3-Like Protein 1; Decision Support Techniques; Drug Therapy, Combination; Epidermal Growth Factor; Female; Humans; Hydroxychloroquine; Infliximab; Interleukin-6; Leptin; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Methotrexate; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor, Type I; Resistin; Serum Amyloid A Protein; Severity of Illness Index; Sulfasalazine; Treatment Failure; Treatment Outcome; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Smoking is pathogenic for rheumatoid arthritis (RA) being tightly connected to the genetic and serological risk factors for this disease. This study aims to understand connections between cigarette smoking and serum levels of IGF1 and adipokines in RA.. Serum levels of IGF1 and adipokines leptin, adiponectin, resistin, and visfatin were measured in two independent cohorts of RA patients from Gothenburg (n = 350) and Leiden (n = 193). An association of these parameters with smoking was tested in a direct comparison and proved by bivariate correlation analysis. The obtained associations were further tested in multivariate regression models where the confounders (age, gender, disease duration, and BMI) were controlled.. The smokers had significantly lower serum levels of IGF1, adiponectin, and leptin compared to never smokers. In regression analysis, smoking and low leptin, but not adiponectin, were associated and predicted low IGF1. Additionally, high disease activity and high BMI increased the probability of low leptin.. The study indicates cigarette smoking as an important cause of a relative IGF1 and leptin deficiency in RA patients. This novel association between smoking and hypoleptinemia may be of importance for long-term prognosis of RA and for prediction of comorbidities.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Female; Humans; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Risk Factors; Smoking

Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis.. Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro.. Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade.. An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

Topics: Adult; Arthritis, Rheumatoid; Chromatography, Liquid; Cytokines; Fatty Acids, Nonesterified; Female; Humans; Leptin; Male; Middle Aged; Resistin; Tandem Mass Spectrometry; Th1 Cells

Topics: Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Diseases; Humans; Leptin

Topics: Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Diseases; Humans; Leptin

To evaluate the effects of physiologically relevant concentrations of multimeric adiponectin isoforms and leptin on the function of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).. FLS, isolated from the synovial tissue of 21 RA patients, were stimulated for 24 h with interleukin (IL)-1β (1 ng/mL) and adiponectin isoforms [fraction enriched with high-molecular-weight (HMW) oligomers and middle-molecular-weight (MMW) hexamers or low-molecular-weight (LMW) trimers, 10 μg/mL each], or leptin (10 ng/mL), either separately or in a combination of IL-1β and the respective adipokine. Moreover, cells were pre-treated for 24 h with adipokines, then stimulated for 8 h with IL-1β. The concentrations of IL-6, IL-8, matrix metalloproteinase (MMP)-3, and dickkopf (DKK)-1, an inhibitor of osteoblastogenesis, in culture supernatants, as well as the concentrations of leptin, HMW, MMW, and LMW adiponectin in sera and synovial fluid (SF) samples, were measured by specific enzyme-linked immunosorbent assays (ELISAs).. In comparison with sera, SF samples contained similar amounts of leptin, lower amounts of total adiponectin but a higher proportion of the LMW isoform. Separately added IL-1β and HMW/MMW adiponectin, but not LMW adiponectin or leptin, up-regulated the release of IL-6, IL-8, and MMP-3 from FLS but no synergy was observed in co-stimulation experiments. However, pre-treatment of FLS with HMW/MMW or LMW significantly raised the IL-1β-triggered secretion of MMP-3 and IL-6 or MMP-3, respectively.. Adiponectin not only triggers pro-inflammatory and pro-destructive activities of rheumatoid FLS but also pre-disposes these cells to a stronger response to IL-1β. Thus, it is likely that adiponectin is more important in the initiation phase than in the chronic phase of RA.

Topics: Adiponectin; Arthritis, Rheumatoid; Cells, Cultured; Female; Fibroblasts; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-1beta; Interleukin-6; Interleukin-8; Leptin; Male; Matrix Metalloproteinase 3; Middle Aged; Molecular Weight; Protein Isoforms; Synovial Membrane

Survivin is an independent prognostic factor for joint destruction in rheumatoid arthritis (RA). However, the expression and function of survivin in RA synoviocytes remain unclear. We certified the expression of survivin in RA synovial tissues and performed the experiment using RA fibroblast-like synoviocytes (RA-FLS) treated with siRNA. As a result, the expression levels of wild type (WT) survivin and the 2B splice variants in RA synovial tissues were higher than those in osteoarthritis tissue samples, and, these variants were highly expressed in RA-FLS. The expression levels of survivin-WT and -2B in the RA-FLS were upregulated by PDGF. Treatment with siRNA against survivin-2B led to decreased viability of PDGF-treated RA-FLS due to cell cycle suppression and apoptosis promotion, while the siRNA against all survivin isoforms did not affect the viability. Moreover, an overexpression of survivin-2B in RA-FLS led to cell proliferation through cell cycle activation and by conferring resistance to apoptosis. In conclusion, survivin-2B has an important role in RA-FLS proliferation. These data suggest that survivin-2B might contribute to rheumatoid synovial hyperplasia, and have the potential as a novel therapeutic target for RA.

Topics: Aged; Apoptosis; Arthritis, Rheumatoid; Becaplermin; Cell Proliferation; Cell Survival; Cells, Cultured; Female; Fibroblasts; Humans; Inhibitor of Apoptosis Proteins; Interleukin-1beta; Leptin; Male; Middle Aged; Osteoarthritis; Protein Isoforms; Proto-Oncogene Mas; Proto-Oncogene Proteins c-sis; RNA Splicing; RNA, Small Interfering; Survivin; Synovial Membrane; Tumor Necrosis Factor-alpha

Remission is the primary aim in the treatment of patients with rheumatoid arthritis (RA). In this study, we aimed to evaluate biomarker profiles of patients in remission by different criteria and compare these profiles with controls.. Serum levels of calprotectin, interleukin 6 (IL-6), type II collagen helical peptide, C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3), resistin, and leptin were measured by ELISA in 80 patients. The patients were in Disease Activity Score at 28 joints with erythrocyte sedimentation rate (DAS28-ESR) remission, and had these characteristics: female/male 54/26, mean age 51.4 ± 12.1 years, mean disease duration 11.4 ± 8.1 years, rheumatoid factor positivity 68.7% (n = 55), anticyclic citrullinated peptide positivity 60.7% (n = 48). These patients were also evaluated for the American College of Rheumatology/European League Against Rheumatism (Boolean) and Simple Disease Activity Index (SDAI) remissions. Additionally, 80 age-, sex-, and comorbidity-matched individuals without rheumatic diseases were included in the study as controls.. At recruitment of 80 patients in DAS28 remission, 33 patients (41.2%) were found in Boolean remission and 39 patients (48.7%) were in SDAI remission. Serum MMP-3, ICTP, resistin, and IL-6 levels of the 80 patients in DAS28 remission were statistically significantly higher than the controls. Patients in Boolean and SDAI remissions had significantly higher serum ICTP, resistin, and IL-6 levels in comparison with the controls.. The 3 commonly used remission criteria of RA are almost similar with regard to patients' biomarker levels. Biomarker profiles of patients may provide complementary information to clinical evaluation of remission and may help to determine the patients under the risk of progression.

Topics: Adult; Age Factors; Analysis of Variance; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; C-Reactive Protein; Case-Control Studies; Disease Progression; Female; Humans; Interleukin-6; Leptin; Leukocyte L1 Antigen Complex; Male; Matrix Metalloproteinase 3; Middle Aged; Prognosis; Remission Induction; Retrospective Studies; Rheumatoid Factor; Risk Assessment; Severity of Illness Index; Sex Factors; Statistics, Nonparametric; Treatment Outcome

Leptin has a prominent role in the development and maintenance of acute and chronic inflammatory states such as rheumatoid arthritis (RA) and obesity. Nevertheless, the association of serum leptin (sLep) and soluble leptin receptor (sLepR) in RA pathogenesis has not been clarified. The purpose of this study was to evaluate the association of sLep, sLepR and leptin production indexes such as sLep/fat mass ratio with clinical activity and biomarkers and anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA compared with body mass index (BMI) matched control subjects.. We included 64 RA patients and 66 controls matched for age, gender and BMI. Subjects were evaluated for BMI, fat mass distribution, sLep, sLepR, sLep/fat mass ratio and sLepR/fat mass ratio. Patients were evaluated for clinical activity and anti-CCP antibodies.. We found two or three fold increased sLep levels, sLep/sLepR ratio and sLep/fat mass ratio in obese anti-CCP positive RA patients vs.. Partial correlations showed that anti-CCP antibodies were correlated with sLep/fat mass ratio (partial r = 0.347, P = 0.033) after adjustment for age, subcutaneous adipose tissue and fat mass.. In preobese and obese RA patients there is and increased production of sLep according to anti-CCP positivity. This phenomenon suggests there is an additive effect of chronic inflammation resulting from RA and obesity in which leptin favors the humoral response against citrullinated proteins. In summary, the data observed in our study suggests sLep could be a surrogate marker of chronicity and humoral immunity in RA in the presence of obesity.

Topics: Adult; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Citrulline; Female; Humans; Leptin; Male; Middle Aged; Obesity; Receptors, Leptin; Young Adult

We have previously shown that overweight may increase the risk of developing rheumatoid arthritis (RA) in autoantibody positive individuals. Adipose tissue could contribute to the development of RA by production of various bioactive peptides. Therefore, we examined levels of adipokines in serum and synovial tissue of subjects at risk of RA.. Fifty-one individuals positive for immunoglobulin M rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibodies (ACPA), without arthritis, were included in this prospective study. Levels of adiponectin, vaspin, resistin, leptin, chemerin and omentin were determined in baseline fasting serum samples (n = 27). Synovial tissue was obtained by arthroscopy at baseline and we examined the expression of adiponectin, resistin and visfatin by immunohistochemistry.. The development of clinically manifest arthritis after follow-up was associated with baseline serum vaspin levels (HR1.5 (95% CI 1.1 to 2.2); p = 0.020), also after adjustment for overweight (HR1.7 (95% CI 1.1 to 2.5); p = 0.016). This association was not seen for other adipokines. Various serum adipokine levels correlated with BMI (adiponectin r = -0.538, leptin r = 0.664; chemerin r = 0.529) and systemic markers of inflammation such as CRP levels at baseline (adiponectin r = -0.449, omentin r = -0.557, leptin r = 0.635, chemerin r = 0.619, resistin r = 0.520) and ESR (leptin r = 0.512, chemerin r = 0.708), p-value<0.05. Synovial expression of adiponectin, resistin and visfatin was not associated with development of clinically manifest arthritis.. In this exploratory study, serum adipokines were associated with an increased inflammatory state in autoantibody-positive individuals at risk of developing RA. Furthermore, serum vaspin levels may assist in predicting the development of arthritis in these individuals.

Topics: Adiponectin; Adult; Arthritis, Rheumatoid; Autoantibodies; Biomarkers; Body Mass Index; Demography; Follow-Up Studies; Humans; Inflammation; Leptin; Middle Aged; Proportional Hazards Models; Serpins; Synovial Membrane

The aim of this study was to determine whether disease activity and the type of therapy differentially modulate serum adipokine levels in patients with rheumatoid arthritis (RA), and whether pre-therapy adipokine levels contribute to resistance to treatment. Fasting blood samples from 40 RA patients were obtained at baseline and six months following therapeutic treatment with disease-modifying antirheumatic drugs (DMARDs) and/or tumor necrosis factor (TNF)-α blockers. Serum levels of adiponectin, leptin, visfatin and resistin were measured by ELISA. Baseline adipokine levels did not exhibit a statistically significant difference when comparing patients with moderate and high disease activity, based on the disease activity score in 28 joints (DAS28). Of all the adipokines, only adiponectin was significantly increased in patients responding to DMARDs and/or TNF-α blocker therapy, based on the American College of Rheumatology 20% improvement criteria (ACR20) at six months (2,964±1,237 to 3,683±1,511 ng/ml, P<0.01). However, adiponectin levels in non-responders did not significantly increase (3,192±2,090 to 3,222±1,150 ng/ml). By contrast, there were no statistically significant changes in leptin, resistin or visfatin levels in either the responders or non-responders. Serum adipokine (adiponectin, leptin, visfatin, and resistin) levels in RA patients did not significantly change following therapy, with the exception of adiponectin. Adipokine levels may not contribute to therapeutic resistance to DMARDs and/or TNF-α blocking agents.

Topics: Adipokines; Adiponectin; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Tumor Necrosis Factor-alpha

We examined the potential impact of demographic characteristics on the independent leptin-metabolic cardiovascular risk factor and leptin-endothelial activation relationships in black and white patients with RA. Leptin concentrations and those of endothelial activation molecules including soluble E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were measured in 217 RA patients (51.6% black). We determined associations in potential confounder and mediator-adjusted mixed regression models. No independent associations between leptin concentrations and cardiovascular risk were present in all patients and either women and men or black and white patients. However, age impacted on several leptin-cardiovascular risk relations (interaction P < 0.05). In patients aged <50 years (lower quartile), after but not before adjustment for waist circumference and body mass index in addition to other confounders, leptin concentrations associated with overall endothelial activation as estimated by an SD (z) score of endothelial activation molecule concentrations (partial R = 0.341, P = 0.04). In patients aged 50-58 years (second quartile), leptin concentrations related to those of HDL cholesterol (partial R = -0.365, P = 0.01) and total cholesterol-HDL cholesterol ratio (partial R = 0.299, P = 0.04), and in those aged 59-63 years (third quartile), paradoxically related to low systolic and mean blood pressure (partial R = -0.438, P = 0.005 and partial R = -0.370, P = 0.02, respectively). Patients with RA aged <50 years experience an independent adiposity-driven leptin-endothelial activation relationship in the absence of leptin-metabolic risk factor associations. Young but not older patients with RA may sustain obesity-induced endothelial activation that is directly mediated by leptin.

Topics: Adult; Age Factors; Aged; Aging; Arthritis, Rheumatoid; Atherosclerosis; Biomarkers; Black People; Chemokine CCL2; Cholesterol, HDL; Comorbidity; Cross-Sectional Studies; E-Selectin; Female; Heart Diseases; Humans; Intercellular Adhesion Molecule-1; Leptin; Male; Metabolic Diseases; Middle Aged; Risk Factors; Vascular Cell Adhesion Molecule-1; White People

Topics: Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Diseases; Humans; Leptin; Risk Factors

Adiponectin and leptin are likely involved in the pathophysiology of rheumatoid arthritis (RA) and therefore potential new therapeutic targets. Adiponectin inhibition could be expected to enhance cardiovascular metabolic risk. However, it is unknown whether RA changes the influence of adipokines on cardiovascular metabolic risk. We determined whether RA impacts on the independent relationships of circulating leptin and adiponectin concentrations with cardiovascular risk factors and carotid intima-media thickness (cIMT) in 277 black African subjects from a developing population; 119 had RA. RA impacted on the relationships of adiponectin concentrations with lipid concentrations and blood pressure, independent of confounders including adiposity (interaction P < 0.05). This translated into an association of adiponectin concentrations with more favorable lipid variables including HDL cholesterol (P = 0.0005), non-HDL cholesterol (P = 0.007), and triglyceride (P = 0.005) concentrations, total cholesterol-HDL cholesterol (P = 0.0002) and triglycerides-HDL cholesterol (P = 0.0003) ratios, and higher systolic (P = 0.0006), diastolic (P = 0.0004), and mean blood pressure (P = 0.0007) in RA but not non-RA subjects. Leptin was not associated with metabolic risk after adjustment for adiposity. The cIMT did not differ by RA status, and adipokine concentrations were unrelated to atherosclerosis. This study suggests that leptin and adiponectin inhibition may not alter overall cardiovascular risk and disease in RA.

Topics: Adipokines; Adiponectin; Aged; Arterial Pressure; Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cholesterol, HDL; Female; Humans; Leptin; Male; Middle Aged; Risk Factors

Dyslipidemia has been implicated in various musculoskeletal diseases, including rheumatoid arthritis (RA). Evidence is emerging that there might be a pathogenic interaction among inflammation, dyslipidemia, and adipokines. We prospectively investigated the association of cumulative lipid levels with radiographic progression of RA. RA patients (n=242) underwent plasma cholesterol assessment at four visits. Disease activity parameters and X-rays of the hands and feet were also serially monitored in these patients. The cumulative inflammatory burden and lipid levels were estimated by time-integrated values. Serum leptin and adiponectin concentrations were determined by ELISA. When patients were divided into three groups according to time-integrated lipid levels, as expected, patients with LDL cholesterol and/or triglyceride levels in the third tertile had persistently higher ESR and CRP levels. In parallel, a more rapid radiographic progression over two years was observed in patients with higher LDL cholesterol and/or triglyceride levels. In multivariate analysis, time-integrated LDL cholesterol was independently associated with radiographic progression. Particularly, the risk of radiographic progression was 5.6-fold in a subgroup with both LDL cholesterol and triglyceride levels in the third tertile. Moreover, LDL cholesterol synergistically increased the adjusted probability of radiographic progression in patients with high serum leptin levels but not in those without. These results demonstrate that LDL cholesterolemia is a novel serum marker that can be used to predict radiographic progression of RA, which seems to be related to circulatory leptin levels. We suggest that personalized and more aggressive anti-rheumatic therapy is required for dyslipidemic subgroups in RA patients.

Topics: Adipokines; Arthritis, Rheumatoid; Blood Sedimentation; C-Reactive Protein; Cholesterol, LDL; Disease Progression; Dyslipidemias; Female; Follow-Up Studies; Humans; Leptin; Logistic Models; Male; Middle Aged; Prognosis; Prospective Studies; Radiography; Risk Factors; Time Factors

Hypertension (HTN), a common modifiable cardiovascular risk factor, is more common in patients with rheumatoid arthritis (RA), but the underlying mechanisms are unclear. We examined the hypothesis that mediators of inflammation and markers of cardiovascular risk are associated with HTN in RA.. We compared measures of inflammation [serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), homocysteine, and leptin concentrations] and insulin resistance [homeostasis model assessment index (HOMA)] in RA patients with (n = 90) and without HTN (n = 79). HTN was defined as blood pressure ≥ 140/90 mm Hg or treatment with antihypertensive therapy. The independent association of markers of interest with HTN was examined using multivariable logistic regression.. Patients with HTN were significantly older and had longer disease duration than those without HTN (both p < 0.001). Concentrations of homocysteine [11.1 (8.5-13.5) μmol/l vs 9.3 (7.8-11.0) μmol/l] were significantly higher in patients with HTN (p < 0.001). After adjustment for age, sex, race, smoking, body mass index, and corticosteroid and nonsteroidal antiinflammatory drugs (NSAID) use, increased concentrations of homocysteine (OR 2.9, 95% CI: 1.5-5.5, p = 0.001), and leptin (OR 2.0, 95% CI: 1.0-3.8, p = 0.046) were significantly associated with HTN, but the 28-joint Disease Activity Score, IL-6, CRP, TNF-α, and HOMA index were not (all p > 0.05).. HTN in patients with RA is not associated with generalized systemic inflammation or insulin resistance, but is associated with increasing concentrations of homocysteine and leptin. The pathogenesis of HTN in RA may involve pathways more regularly associated with fat and vascular homeostasis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Female; Humans; Hypertension; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Risk Factors; Tumor Necrosis Factor-alpha

Reports suggest leptin, which was initially described as a hormone that regulates food intake and energy balance, has an intimate relationship, and interacts with the immune system. Leptin consumption in the synovial cavity in patients with rheumatoid arthritis (RA) reported to have protective effect against erosion. To determine the difference in serum leptin and synovial/serum leptin ratio between RA and control and to assess whether these parameters correlate with systemic inflammation in RA. Also, the hypothesis that synovial/serum leptin ratio could be linked to joint erosion in RA was evaluated. The study subjects consisted of 40 consecutive patients with RA, 30 patients of them had knee effusion, and 30 controls. Ten of these controls had acute knee injury and their synovial fluid was obtained for comparison of synovial/serum leptin ratio with patients with RA. The mean serum leptin in patients with RA was significantly higher than controls. Also, the synovial leptin and synovial/serum leptin ratio in the RA patients with effusion was significantly higher than in the 10 control subjects with traumatic effusion. Serum leptin in the 30 RA patients with effusion was higher than the matched synovial leptin. In RA patients with effusion, synovial/serum leptin ratio was also significantly higher in RA patients with erosion than RA patients without erosion. Serum leptin level and synovial/serum leptin ratio are significantly correlated with the RA duration, DAS28, ESR, CRP, TNF-α, and IL-6. Finally, in regression analysis, only the synovial/serum leptin ratio was positively associated with erosion in patients with RA. In RA, there is a significant increase in circulating leptin levels and synovial/serum leptin ratio compared to non-RA controls. Serum leptin and synovial/serum leptin ratio are significantly in erosive RA than non-erosive RA. Both parameters are correlated with disease duration and parameters of RA activity. In regression analysis, only the synovial/serum leptin ratio was positively associated with erosion in patients with RA. These results indicate that local consumption of leptin in the joint cavity has a protective role against the destructive course of RA.

Topics: Adult; Arthritis, Rheumatoid; Exudates and Transudates; Female; Humans; Joints; Leptin; Male; Prospective Studies; Synovitis; Young Adult

TNF-α is one of the key proinflammatory cytokines in pathogenesis of rheumatoid arthritis (RA). TNF-α was also found to enhance synthesis of leptin. Leptin is mainly adipocyte-derived hormone controlling appetite and energy expenditure. It acts through inhibition of neuropeptide Y secretion. It is possible that TNF-α-induced leptin secretion contributes to body mass reduction in patients with RA. The study was designed to determine the influence of inactivation of the TNF-α with infliximab on plasma leptin and neuropeptide Y concentrations in patients with RA. Sixteen female patients with RA treated with infliximab and 16 healthy women were investigated. Plasma leptin and neuropeptide Y concentrations were determined before, during and after 1 year management of the patients with infliximab and were compared with body mass index and body fatty and lean mass. There was no difference in plasma leptin concentration between the rheumatoid patients before therapy and the controls (15.6 ± 1.85 and 14.5 ± 2.15 ng/ml, respectively). Neuropeptide Y concentration was higher in the patients than in the controls (54.5 ± 3.96 and 24.8 ± 2.80 pmol/l, respectively). Treatment with infliximab resulted in enhancement in leptin concentration (18.5 ± 2.34 ng/ml) and a slight increase in neuropeptide Y concentration (58.7 ± 4.66 pmol/l). Physiological relationship between leptin and body mass was shown in the patients and was not altered during the treatment. There was no significant correlation between the disease activity and plasma leptin or neuropeptide Y concentrations.

Topics: Adult; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Body Mass Index; Drug Therapy, Combination; Female; Humans; Infliximab; Leptin; Methotrexate; Neuropeptide Y; Prednisone; Treatment Outcome; Tumor Necrosis Factor-alpha

Body fat is an important source of hormones and cytokines (adipokines) that not only regulate the energy balance, but also regulate the inflammatory and immune responses. This study investigated the association of clinical conditions with serum levels of adipokines in patients with rheumatoid arthritis.. Serum levels of resistin, leptin, and adiponectin were measured by enzyme-linked immunosorbent assay in 141 patients (110 women) who fulfilled the 1987 revised criteria of the American Rheumatism Association for the diagnosis of rheumatoid arthritis and in 146 normal controls (124 women). Then the correlations between adipokine levels and clinical parameters were evaluated.. The serum resistin level did not differ between the patients and controls. However, serum leptin levels were significantly higher in male and female rheumatoid arthritis patients than in the corresponding controls, while the serum adiponectin level was significantly higher in female patients than in female controls. Multivariate analysis revealed that predictors of an elevated resistin level were female sex and C-reactive protein (CRP), while the leptin level was related to the body mass index and CRP. Predictors of an elevated adiponectin level were the use of prednisolone and CRP, however, CRP was negatively associated with adiponectin in patients with rheumatoid arthritis.. The serum levels of resistin and leptin were positively associated with CRP level in patients with rheumatoid arthritis, suggesting that these adipokines may act as pro-inflammatory cytokines in this disease. The serum adiponectin level was elevated in the patients, however, it was negatively associated with CRP level. In addition, the serum levels of resistin, leptin, and adiponectin were also associated with female sex, BMI and the use of prednisolone, respectively.

Topics: Adiponectin; Adult; Aged; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; Body Mass Index; C-Reactive Protein; Case-Control Studies; Female; Humans; Japan; Leptin; Male; Middle Aged; Multivariate Analysis; Resistin; Sex Characteristics

A potential link between obesity, circulating leptin levels and autoimmune disease symptoms suggests that targeting the leptin receptor (ObR) might be a viable novel strategy to combat rheumatoid arthritis (RA). However, studies in animal models and evaluation of clinical cases did not provide clear view on leptin's involvement in RA. To validate ObR as RA target, we used our peptide-based ObR agonists and antagonist in different in vitro and in vivo models of the disease. In human peripheral blood mononuclear cells, leptin and its agonist fragment, desI(2)-E1/Aca, moderately induced constitutive activation of a major proinflammatory transcription factor, NF-κB, while the ObR antagonist peptide Allo-aca inhibited the process. Leptin administration itself did not induce arthritis in rats, but worsened the clinical condition of mice given K/BxN serum transfer arthritis. Simultaneous administration of Allo-aca reduced leptin-dependent increase in disease severity by more than 50%, but the antagonist was ineffective when injected with a 3-day delay. In rats inflicted with mild adjuvant-induced arthritis, both leptin and Allo-aca reduced the extent of joint swelling and the number of arthritic joints. In a more aggressive disease stage, Allo-aca decreased the number of arthritic joints in a dose-dependent manner but did not affect other arthritis markers. In summary, leptin exerts diverse effects on RA depending on the experimental model. This might reflect the heterogeneous character of RA, which is differently impacted by leptin and is unmasked by ObR antagonism. Nevertheless, the results suggest that ObR antagonists might become useful therapeutics in leptin-sensitive early stages of RA.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Female; Humans; Leptin; Leukocytes, Mononuclear; Mice; Mice, Transgenic; Oligopeptides; Rats; Receptors, Leptin

Adipose tissue is regarded as an active metabolic and endocrine organ producing adipokines. The purpose of the study was to evaluate adiponectin and leptin concentrations in rheumatoid arthritis (RA) patients (pts) in relation to disease duration and activity. The study group consisted of 80 RA pts. Serum adiponectin and leptin concentrations remained within normal ranges. Adiponectin concentration correlated positively both with the age and disease duration. Both adipokines levels correlated negatively with glomerular filtration rate. There were significant positive correlations between adipokines' concentrations and lipid profile components (between adiponectin and HDL-cholesterol, leptin and total cholesterol and LDL-cholesterol). In pts with long-standing RA, there was a negative correlation between adiponectin and numbers of tender, swollen joints and a positive relationship between leptin level and DAS28. The results confirm adipokines' involvement in the process of inflammation and atherosclerosis: protective and antiinflammatory adiponectin effect and proatherogenic and proinflammatory leptin function.

Topics: Adiponectin; Adult; Age Factors; Age of Onset; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Cholesterol, HDL; Cholesterol, LDL; Female; Glomerular Filtration Rate; Humans; Leptin; Male; Middle Aged; Predictive Value of Tests; Severity of Illness Index; Young Adult

The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA.. The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines.. Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05).. Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.

Topics: Adipokines; Adiponectin; Arthritis, Rheumatoid; Calcinosis; Calcium; Coronary Artery Disease; Cytokines; Female; Humans; Inflammation Mediators; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Prevalence; Resistin; Risk Factors

Topics: Adult; Arthritis, Rheumatoid; Biomarkers; Cytokines; Female; Follow-Up Studies; Humans; Leptin; Male; Middle Aged

In obese rheumatoid arthritis (RA) patients inflammatory mechanisms and cardiovascular secondary disorders are possibly related to changed expression of adipocytokines. Various adipocytokines and inflammatory parameters were examined in 112 patients (23.2% men; 76.8% women) suffering from RA: leptin, adiponectin, visfatin, sCD40 L, CRP, and ESR. Average BMI was 27.6 (+/-5.6). Leptin and BMI as well as visfatin and BMI correlated positively, BMI and adiponectin, however, showed a negative correlation. Significant differences between normal-weight and obese RA patients were found in both leptin and adiponectin measurements. Visfatin showed a positive correlation with CRP; sCD40 ligand which is a marker for increased T-cell activity correlated with CRP and ESR. Patients with low adiponectin levels (<10 microg/ml) more often suffered from cardiovascular diseases (28.6%) than those with enhanced adiponectin (14.3%). Increased pro-inflammatory leptin and decreased anti-inflammatory adiponectin in obese RA patients can be associated with RA activity and enhanced cardiovascular risk.

Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Blood Sedimentation; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; CD40 Ligand; Cytokines; Female; Humans; Inflammation Mediators; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Reference Values; Risk Factors; Statistics as Topic; Young Adult

This study was designed to investigate the serum and synovial fluid leptin levels, and inflammatory markers in rheumatoid arthritis (RA) patients. Serum and synovial fluid leptin levels were significantly higher (P > 0.05) in RA patients than control group; RA patients with moderate disease activity (DAS < 2.7) having significantly higher leptin levels (P > 0.05) than those with low disease activity (DAS < 2.7). Leukocytes and erythrocyte sedimentation rate (ESR) were found to be significantly higher in moderate disease activity RA group compared to low activity group (P > 0.05, P < 0.001, respectively). Serum leptin level is found to be independent of age and inflammatory markers. ESR is positively correlated with DAS activity and CRP values. Our finding of no correlation between leptin and BMI shows that regulation of leptinemia is complex, and leptin levels cannot be used to assess RA activity.

Topics: Adult; Age Factors; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; Body Mass Index; Chemotaxis, Leukocyte; Cytokines; Erythrocytes; Female; Humans; Inflammation Mediators; Joints; Leptin; Leukocytes; Male; Middle Aged; Obesity; Predictive Value of Tests; Synovial Fluid; Up-Regulation

To evaluate the association between circulating leptin and bone mineral density (BMD) in patients with rheumatoid arthritis (RA).. One-hundred thirty postmenopausal women with RA were assessed for body mass index (BMI), disease characteristics, history of drug use, rheumatoid factor, and erythrocyte sedimentation rate (ESR). BMD (g/cm(2)) was determined in the hip and spine by DEXA. Serum leptin concentrations were measured by ELISA. Spearman's correlation coefficients (rho) were determined between BMD and leptin and other variables. A multiple regression analysis was used to adjust for confounders.. Patients' serum leptin levels varied widely (range 2-128 ng/ml). Thirty-three patients (25%) had osteoporosis. Higher levels of leptin correlated significantly with BMD in the lumbar spine (rho = 0.17, p = 0.04) and total hip (rho = 0.21, p = 0.01). The variables that were negatively correlated with BMD were age, duration of menopause, and ESR. After adjustment for confounders, leptin was no longer associated with BMD. In the multivariate model, factors that remained associated with BMD in the total hip were age (p = 0.021) and BMI (p = 0.003); and the factors that remained associated with BMD in the lumbar spine were BMI (p = 0.03) and ESR (p = 0.01).. No relevant association was found between circulating leptin levels and BMD in patients with RA in this cross-sectional study. Followup studies are needed to evaluate whether abnormal leptin levels confer a risk for fractures due to osteoporosis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Bone Density; Cross-Sectional Studies; Humans; Leptin; Middle Aged; Osteoporosis; Statistics, Nonparametric

Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA.. We studied 58 RA patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin and adiponectin were measured.. Patients with RA had increased adiponectin (p<0.001) and similar leptin concentrations compared with the controls. Leptin concentrations were significantly higher in patients with high BMI (p<0.001) and correlated positively with BMI at all timepoints (r>0.75). In contrast, serum adiponectin tended to be higher in lean RA patients and did not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity (Disease Activity Score 28). Short or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months of therapy (p<0.025).. In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory markers in regulating adipocytokine patterns in RA.

Topics: Adiponectin; Adult; Aged; Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Body Mass Index; Female; Humans; Infliximab; Leptin; Male; Middle Aged; Severity of Illness Index; Statistics as Topic; Tumor Necrosis Factor-alpha

Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA.. We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNFalpha]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFalpha, IL-6, and CRP).. Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (rho = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67).. Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Topics: Adipokines; Adiponectin; Adult; Aged; Arthritis, Rheumatoid; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Female; Foot Joints; Hand Joints; Humans; Interleukin-6; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Radiography; Resistin; Tumor Necrosis Factor-alpha

Recent reports have suggested that increasing adiposity may protect against radiographic damage in rheumatoid arthritis (RA). We explored the role of serum adipokines (adiponectin, resistin, and leptin) in mediating this association.. Patients with RA underwent total-body dual x-ray absorptiometry for measurement of total and regional body fat and lean mass, abdominal computed tomography for measurement of visceral fat area, and radiographs of the hands and feet scored according to the modified Sharp/van der Heijde (SHS) method. Serum levels of adipokines were measured and cross-sectional associations with radiographic damage were explored, adjusting for pertinent confounders. The associations of measures of adiposity with radiographic damage were explored with the introduction of adipokines into multivariable modeling as potential mediators.. Among the 197 patients studied, adiponectin demonstrated a strong association with radiographic damage, with the log SHS score increasing by 0.40 units for each log unit increase in adiponectin (P = 0.001) after adjusting for pertinent predictors of radiographic damage. Adiponectin independently accounted for 6.1% of the explainable variability in SHS score, a proportion comparable with rheumatoid factor, and greater than HLA-DRB1 shared epitope alleles or C-reactive protein levels. Resistin and leptin were not associated with radiographic damage in adjusted models. An inverse association between visceral fat area and radiographic damage was attenuated when adiponectin was modeled as a mediator. The association of adiponectin with radiographic damage was stronger in patients with longer disease duration.. Adiponectin may represent a mechanistic link between low adiposity and increased radiographic damage in RA. Adiponectin modulation may represent a novel strategy for attenuating articular damage.

Topics: Absorptiometry, Photon; Adiponectin; Adiposity; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Cohort Studies; Cross-Sectional Studies; Female; Foot Joints; Hand Joints; Humans; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Resistin; Severity of Illness Index

Rheumatoid arthritis (RA) is a multisystem disease with high rates of morbidity and mortality. In recent years, there has been increasing focus on the growing rates of cardiovascular disease (CVD) in RA, over and above expected levels allowing for 'traditional' risk factors. In this paper the impact of CVD in RA, the relative contributions of traditional risk factors and novel risk factors (including homocysteine, oxidised low-density lipoprotein, high-sensitivity C-reactive protein and leptin), and the need to address cardiovascular risk in the fight against premature death from coronary artery and stroke disease in RA are discussed.

Topics: Arthritis, Rheumatoid; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Comorbidity; Coronary Artery Disease; Endothelium, Vascular; Homocysteine; Humans; Leptin

Topics: Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Biomarkers; Ghrelin; Humans; Leptin; Vasculitis

Adipocytokines are hormone and cytokine like substances produced mainly from white adipose tissue. A relation between plasma adipocytokines and many inflammatory disorders including rheumatoid arthritis (RA) had been investigated. This work was done to investigate the systemic behavior of the main adipocytokines at the plasma level as well as its local behavior at the synovial fluid level in patients with RA and osteoarthritis (OA). The study had been conducted on 32 patients with RA and 18 patients with OA. Paired blood and synovial fluid samples had been collected from all patients and level of plasma and synovial fluid (SF) leptin, adiponectin and resistin had been quantitated by enzyme linked immunosorbent assay (ELISA). Results had been compared between RA group and OA group. Adipocytokines had also been compared in patients with erosive and non-erosive disease and had been related to clinical and laboratory markers of activity. Plasma resistin and BMI-corrected plasma leptin were significantly higher in RA group. Female patients showed significantly higher plasma leptin, even after correction to BMI. Studied SF adipocytokines were significantly higher in RA group and correlated positively with synovial fluid WBCs. Comparing plasma and SF results showed a significant increase in SF resistin especially in RA group and a significant drop of SF adiponectin especially in OA group. In conclusion, Adipocytokines are probably involved in inflammatory and degenerative articular disease. The different behavior between plasma and SF would suggest a pro-inflammatory role for resistin and chondro-protective role for adiponectin.

Topics: Adipokines; Adiponectin; Adult; Arthritis, Rheumatoid; Blood Sedimentation; Body Mass Index; C-Reactive Protein; Cell Count; Female; Humans; Leptin; Leukocytes; Male; Middle Aged; Osteoarthritis; Resistin; Sex Characteristics; Synovial Fluid

Leptin is a peptide hormone with the tertiary structure of a cytokine, which not only regulates body weight by inhibiting food intake, but also modulates inflammatory and immune responses. The aim of the study was to investigate if there are connections between leptin concentrations and parameters of nutritional status and disease activity in a group of rheumatoid arthritis (RA) patients. The study group consisted of 37 patients. The mean leptin serum concentration was significantly higher in women than in men. The leptin concentrations correlated positively with BMI only in women with RA. The leptin concentrations were significantly higher in patients with erosive RA. Assessing the group of patients with long-standing RA (duration > 10 years), we found that leptin levels were significantly higher in patients with higher disease activity than in those with DAS28 < or = 5,1; there was also a positive correlation between serum leptin concentration and the value of DAS28, ESR and the number of tender joints. The results suggest that some important dependence exists between the risk of aggressive course of RA and increased leptin levels.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Blood Sedimentation; Body Mass Index; C-Reactive Protein; Female; Humans; Leptin; Male; Methotrexate; Middle Aged; Time Factors

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.

Topics: Adaptor Proteins, Signal Transducing; Arthritis, Rheumatoid; Binding Sites; Cells, Cultured; Fibroblasts; Gene Expression Regulation; Histones; Humans; Insulin Receptor Substrate Proteins; Interleukin-8; Janus Kinase 2; Leptin; NF-kappa B; Osteoarthritis; p300-CBP Transcription Factors; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Synovial Membrane

Leptin is an adypocyte derivated peptide hormone that plays a major role in preventing obesity development by the effects at the hypothalamic level. In our study leptin levels of 41 rheumatoid arthritis (RA) patients and 25 healthy subjects as control group were assessed. Synovial fluid from 21 RA patients were collected to detect leptin levels. Synovial fluid and plasma leptin levels were analysed and correlated with RA duration, ESR, CRP, X ray changes (erosive or non-erosive disease) and negative or positive test for rheumatoid factor. There wasn't any significant difference at plasma leptin levels between RA patients (3.91 +/- 6.15) and control group (4.94 +/- 6.44) (p > 0.05). Plasma leptin levels were correlated with body mass index (BMI) in both healthy subjects and RA patients (r = 0.37; p = 0.018). Therefore in RA patients, plasma and synovial fluid leptin levels were not correlated with disease duration, ESR, CRP, negative or positive test for rheumatoid factor and erosive or non-erosive disease (p > 0.05). In conclusion leptin is correlated with BMI both in RA patients and healthy individuals but no considerable relation with disease activity.

Topics: Adult; Arthritis, Rheumatoid; Biomarkers; Body Mass Index; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Synovial Fluid

We investigated whether serum leptin levels are elevated in patients with active rheumatoid arthritis (RA) and whether these levels correlate with disease activity. Fifty RA patients were enrolled in this study, and their disease activity was assessed using the disease activity score 28 (DAS28). The patients were divided into two groups according to this score: a high activity group with DAS28 > 3.2 (n = 26) and a low activity group with DAS28

Topics: Adolescent; Adult; Arthritis, Rheumatoid; Biomarkers; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Premenopause; Severity of Illness Index

Leptin is a peptide hormone that has an essential role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. The role of leptin in the modulation of the immune response and inflammation has been regarded as important. In rheumatoid arthritis (RA) patients it was reported that fasting leads to an improvement of clinical and biological measures of disease activity, which was associated with a marked decrease in serum leptin. These features suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans. In this study we assessed serum leptin levels in RA and osteoarthritis (OA) patients and found a correlation between serum leptin level and other markers as well as bone mass density changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA and 30 OA patients who constituted the control group. Serum leptin level was determined using the DRG Leptin ELISA Kit-a solid phase enzyme-linked immunosorbent assay based on the sandwich principle. The serum level of leptin in RA patients ranged from 1.8 to 81.1 ng/ml and median value was 11.2. There was a positive correlation between body mass index (BMI) of RA patients and serum level of leptin (correlation coefficients Spearman's r = 0.81). According to correlation coefficients, serum leptin level is independent of age of RA patients, stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration as well as value of titre of the Waaler-Rose, disease activity score (DAS 28) value and presence of rheumatoid nodules. There was a negative correlation between serum leptin level and glomerular filtration rate (GFR). No correlation between the serum leptin level and T-score was found. An influence of steroid treatment on the serum leptin level was not shown. The median serum leptin level in OA patients was 9.2 ng/ml. There was a positive correlation between body mass index of OA patients and serum level of leptin (correlation coefficients Spearman's r = 0.57). No correlation was found between serum leptin level and patient's age, duration of disease and value of laboratory data. There were no correlations between serum leptin level and visual analogue pain scale (VAS) for the lower-limb afflicted patients as well as stage of disease according to Kellgren and Lawrence's score in OA patients. There was a negative correlation between serum leptin level and T-score valu

Topics: Adult; Age Factors; Aged; Arthritis, Rheumatoid; Body Mass Index; Case-Control Studies; Cohort Studies; Female; Humans; Leptin; Male; Middle Aged; Osteoarthritis; Severity of Illness Index; Statistics as Topic

Rheumatoid arthritis is a chronic autoimmune inflammatory condition characterised by polyarthritis and severe change in body mass and neuroendocrine environment.. To investigate plasma levels of adipocytokines (leptin, adiponectin, visfatin and resistin) in patients with rheumatoid arthritis and to compare them with levels in healthy controls.. Adiponectin, resistin, visfatin and leptin concentrations were measured in 31 patients with rheumatoid arthritis and 18 healthy controls by using specific enzyme-linked immunosorbent assays.. Patients with rheumatoid arthritis showed considerably higher plasma levels of leptin, adiponectin and visfatin than healthy controls. No marked difference was observed in resistin levels between patients and controls.. A marked increase in plasma levels of leptin, adiponectin and visfatin was noted in patients with rheumatoid arthritis, whereas resistin levels were similar to those observed in healthy controls. Coordinated roles for adiponectin, leptin and visfatin are suggested in the modulation of the inflammatory environment in patients with rheumatoid arthritis, whereas the lack of modulation in resistin levels is predictive of an irrelevant role for this peptide, suggesting that resistin level is probably not one of the main signals associated with the pathogenesis of this disease.

Topics: Adiponectin; Adult; Arthritis, Rheumatoid; C-Reactive Protein; Cytokines; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Peptide Hormones; Resistin

Topics: Adalimumab; Adiponectin; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Female; Humans; Leptin; Male; Middle Aged; Tumor Necrosis Factor-alpha

This study was performed to evaluate serum leptin levels in rheumatoid arthritis (RA) patients and investigate the correlation with serum tumor necrosis factor alpha (TNF-alpha) levels and clinical and laboratory parameters of disease activity.. Fifty patients with RA and 34 control subjects were included. Disease activity score 28 (DAS28) was calculated for each patient. Laboratory activity was assessed by examining erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Immunoradiometric assay was used for measuring serum leptin levels (ng/mL). Serum TNF-alpha levels (pg/mL) were measured by sandwich enzyme-linked immunosorbent assay method in 41 of 50 RA patients and in 24 control subjects.. Age, sex and body mass index (BMI) did not show a statistically significant difference between RA and control subjects (P > 0.05). Serum leptin levels were higher in RA (P = 0.000). In RA patients, there were no correlations between serum leptin levels and disease duration, swollen and tender joint counts, DAS28, CRP, ESR, serum TNF-alpha levels, oral glucocorticoid and methotrexate usage (P > 0.05). There was no statistically significant serum leptin level difference between patients with high disease activity and mild and low disease activity (P = 0.892). Serum leptin levels positively correlated with BMI in both patient and control groups (P < 0.05). In both groups, mean serum leptin levels were higher in women than men.. Even though serum leptin levels were found to be significantly higher in RA patients than in control subjects in this study, there was no correlation between serum leptin levels and TNF-alpha levels, clinical and laboratory parameters of disease activity. However serum leptin levels positively correlated with BMI in both patient and control groups. In RA, circulating leptin levels do not seem to reflect disease activity.

Topics: Arthritis, Rheumatoid; Body Mass Index; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoradiometric Assay; Leptin; Male; Middle Aged; Severity of Illness Index; Tumor Necrosis Factor-alpha

Hormonal factors playing a role in bone mass and body composition have been rarely assessed in rheumatoid arthritis (RA). In this study, we aimed to evaluate the growth hormone (GH)-insulin-like growth factor-I (IGF-I)-insulin-like growth factor binding protein-3 (IGFPB-3) axis and serum leptin levels in patients with RA and to determine whether these hormonal/growth factors may influence bone mass and body composition in RA.. Serum GH, IGF-I, IGFPB-3 and leptin were evaluated in 38 corticosteroid-treated RA patients, 14 non-RA patients under corticosteroids (corticosteroid controls, CC) and 32 healthy controls (HC). Bone density was evaluated using dual X-ray absorptiometry (DEXA), and expressed as bone mineral density (BMD), and quantitative ultrasound (QUS). Body composition was assessed by DEXA.. The three groups differed regarding femoral neck, total body BMD, lean mass and QUS parameters with lower values in the RA group (all P < or = 0.05). Growth hormone was higher in RA patients (P=0.0001) while IGF-I and IGFBP-3 did not differ between the three groups. In RA patients there was a tendency to high serum leptin levels and leptin strongly correlated with fat mass (r=0.83, P<0.0001), but not with bone mass measurements or inflammatory parameters. There were no differences for lean mass, GH and leptin between CC and HC.. Our results suggest that these GH and leptin modifications could have an influence on both bone mass and body composition in RA.

Topics: Absorptiometry, Photon; Adrenal Cortex Hormones; Adult; Arthritis, Rheumatoid; Body Composition; Bone Density; Female; Femur Neck; Human Growth Hormone; Humans; Inflammation Mediators; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Lumbar Vertebrae; Male; Middle Aged; Severity of Illness Index

Hypoandrogenicity is common in obesity and in chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Adrenal androgens such as androstenedione (ASD) and dehydroepiandrosterone (DHEA) sulphate are low, which partly depends on the influence of TNF in chronic inflammatory diseases. Leptin is stimulated by TNF and is associated with hypoandrogenicity in non-inflammatory conditions.. To study the interrelation between serum levels of leptin and adrenal steroids in SLE and RA.. In a retrospective study, serum levels of leptin, ASD, DHEA, and 17-hydroxyprogesterone (17OHP) were measured by ELISA, and serum levels of cortisol by radioimmunoassay in 30 patients with RA, 32 with SLE, and 54 healthy control subjects (HS).. In SLE and RA but not HS, serum levels of ASD correlated negatively with serum levels of leptin (p<0.01) independently of prior prednisolone treatment in patients with SLE (p = 0.013) and tended to be independent of prednisolone in patients with RA (p = 0.067). In a partial correlation analysis, this interrelation remained significant after controlling for daily prednisolone dose in both patient groups. In both patient groups, serum leptin levels correlated negatively with the molar ratio of serum ASD/serum cortisol and serum ASD/serum 17OHP, and positively with the molar ratio of serum DHEA/serum ASD.. The negative correlation of serum leptin and ASD or, particularly, ASD/17OHP, together with its known anti-androgenic effects indicate that leptin is also involved in hypoandrogenicity in patients with SLE and RA. Leptin may be an important link between chronic inflammation and the hypoandrogenic state.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Androgens; Androstenedione; Arthritis, Rheumatoid; Case-Control Studies; Dehydroepiandrosterone Sulfate; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydrocortisone; Leptin; Lupus Erythematosus, Systemic; Male; Radioimmunoassay; Retrospective Studies

Topics: Animals; Arthritis, Rheumatoid; Autoimmunity; B-Lymphocytes; Cytokines; Humans; Leptin; Models, Animal; Receptors, Cell Surface; Receptors, Leptin; Th1 Cells

Leptin has been shown to participate in bone remodelling and leptin substitution reported to have a protective effect in experimental septic arthritis.. To assess leptin levels in inflamed joints and plasma of patients with RA.. Leptin concentrations were assessed in matched blood and synovial fluid samples from 76 patients with RA. Blood samples from 34 healthy subjects acted as additional controls. Results were analysed and correlated with duration and activity of RA, x ray changes, and treatment at time of sampling.. In patients with RA, leptin levels were significantly higher in plasma than in synovial fluid samples obtained simultaneously and higher than in control samples. Plasma and synovial fluid leptin levels correlated strongly. Locally in the joint, leptin levels were related to WBC count. Such a relation was not seen in the bloodstream. Leptin levels were not related to sex, age, or disease duration. Difference between leptin levels in plasma and synovial fluid was greater in non-erosive arthritis (5.1 (SEM 1.2) v 3.7 (0.9) ng/ml, p=0.006), than in patients with erosive joint disease (6.2 (1.0) v 5.4 (0.8) ng/ml, NS). Methotrexate treatment was associated with relatively high plasma leptin levels, while treatment with other DMARDs was associated with lower leptin levels than in patients receiving no DMARD treatment (p=0.0005).. Leptin production was significantly increased in patients with RA compared with healthy controls. Synovial fluid leptin levels were significantly lower than in matched plasma samples, suggesting an in situ consumption of this molecule.

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Synovial Fluid

Topics: Adiponectin; Aged; Arthritis, Rheumatoid; Cytokines; Female; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Knee Joint; Leptin; Male; Osteoarthritis, Knee; Proteins; Resistin; Signal Transduction; Synovial Fluid

The prospective, cross-sectional study was undertaken to evaluate the relation between the fat mass and serum leptin level in patients with rheumatoid arthritis (RA). Low body mass and anorexia are commonly found in patients with RA. Inflammatory cytokines may significantly influence the secretion of anorectic hormone--leptin--that was confirmed in both experimental and clinical studies. Fifty-two non-diabetic and non-obese patients (38 females, 14 males) were studied. Mean age was 56 +/- 11 years and mean body mass index (BMI) 24.6 +/- 4.1 kg/m2. The disease activity score (DAS) was 3.9 +/- 1.4; range 1.4-7.4, and disease duration 8.1 +/- 6.7 years. Serum leptin was measured by ELISA and body composition by double X-ray densitometry. Mean serum leptin concentration was 2.8 +/- 1.4 ng/ml in patients with RA was lower than in the control group (4.2 +/- 2.0). In a simple regression analysis leptin did not correlate with BMI (R Spearman = 0.01), C-reactive protein (R = 0.08), total fat mass (R = 0.08), trunk fat (R = 0.05), limbs fat (R = 0.09) and DAS (R = -0.17). This relation was also not influenced by gender or type of immunosuppressive therapy. In a multiple regression model none of the independent variables explained the significant portion of variance of serum leptin. It is concluded that the physiologic relation of serum leptin to body fat stores is not present in patients with RA.

Topics: Aged; Arthritis, Rheumatoid; Body Composition; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Prospective Studies; Regression Analysis; Risk Factors; Weight Loss

Leptin, a 16-kD protein of the ob gene product, is produced by adipose tissue and acts on the hypothalamus to suppress neuropeptide Y secretion which reduces the appetite. It has been demonstrated that serum leptin levels in healthy subjects are correlated with body mass index(BMI). Leptin is also produced by stimulation of inflammatory cytokines such as tumor necrosis factor(TNF)-alpha and interleukin(IL)-1. Rheumatoid arthritis(RA) is one of the chronic inflammatory diseases in which high serum cytokine levels are noted. In this study, we measured serum leptin levels(s-leptin) by RIA kit in 20 healthy subjects (10 males and 10 females) and 49 RA patients(14 males and 35 females) and the markers for joint inflammation such as ESR and CRP. There was no difference in s-leptin between controls(male: mean +/- SD = 5.6 +/- 3.0 ng/ml; female: 7.8 +/- 4.5 ng/ml) and RA patients(male: 4.9 +/- 3.2 ng/ml; female: 9.1 +/- 5.7 ng/ml). S-leptin was correlated with BMI in both healthy subjects and RA patients. However, there was no correlation between s-leptin and the values of ESR or CRP, disease stages in RA patients. In conclusion, s-leptin in RA patients reflects BMI but not joint inflammation.

Topics: Adult; Arthritis; Arthritis, Rheumatoid; Body Mass Index; Female; Humans; Leptin; Male; Middle Aged

Leptin, the ob gene product, has been proposed as a mediator of inflammatory cytokine-dependent decreased food intake and cachexia in rodents. In humans, leptin serum levels increase after administration of tumor necrosis factor-alpha (TNF-alpha) or interleukin-2 or during septicemia. However, the effect of human chronic inflammatory disease on serum leptin is unknown. We therefore determined the serum leptin level (radioimmunoassay), body mass index (BMI), percent body fat ([%BF] bioelectrical impedance analysis), and disease activity (Disease Activity Score [DAS]) in 58 patients with rheumatoid arthritis (RA) and 16 controls. The BMI, %BF, serum leptin, and ratio of leptin to %BF (leptin/%BF) did not differ significantly in 25 patients with moderate RA activity (DAS, 3.6 +/- 0.5), 33 patients with low RA activity (DAS, 1.8 +/- 0.5), and controls. A positive correlation for serum leptin and %BF was detected in all groups. Our data indicate that in RA, a human chronic cytokine-mediated inflammatory disease, the serum leptin level is directly related to %BF but not to disease activity.

Topics: Adipose Tissue; Adult; Aged; Arthritis, Rheumatoid; Body Mass Index; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Proteins; Radioimmunoassay; Severity of Illness Index