Table 2: Synthesis of evidence of chronic low-grade inflammation being associated with conditions that may coexist with a diagnosis of osteoarthritis.

Alzheimer’s disease

Giunta et al., 2008
Journal of Neuroinflammation [42]
Inflammaging as a prodrome to Alzheimer’s diseaseReview
The immunological aspects of aging related to Alzheimer’s Disease (AD), that is, the increased innate immunity by cells of the mononuclear
Articles reported the characterization the aging immune response related to the concept of inflammaging (low-grade chronic up-regulation of pro-inflammatory response)
Specific search strategy unspecified
Conditions of increased innate immune response with overproduction of pro-inflammatory proteins are related to healthy aging and AD
People who age “well” have anti-inflammaging mechanisms and biomarkers that counter the adverse immune response of inflammaging
Countering inflammaging may prevent or treat the symptoms of AD
Veerhuis, 2011
Current Alzheimer Research [43]
Histological and direct evidence for the role of complement in the neuroinflammation of AD (AD-Alzheimer’s disease)Histologic and direct evidenceSynthesis and secretion of reactive oxygen species (ROS), cytokines, chemokines, and other potentially neurotoxic agents by the glial cells implicated in
AD
In AD, there are brain areas with amyloid deposits and complement activation products
Complement regulatory proteins are found in brain parenchyma and are upregulated, especially under inflammatory conditions
Evidence from immunohistochemical, in vitro and animal studies points to role for complement activation
In chronic low-grade inflammatory conditions, such as in AD, complement activation proceeds, leading to sustained glial cell activation and neurodegenerative changes
Candore et al., 2010
Current Pharmacology Designs [44]
Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievementReviewSearch strategy unspecifiedEvidence supports that low-grade systemic inflammation characterizes ageing and that inflammatory markers are significant predictors of mortality with ageingElucidation of ageing pathophysiology to disentangle age-related low-grade inflammation will provide evidence to develop drugs to delay ageing process

Asthma

Chou et al., 2011
Journal of Sex Medicine [45]
Asthma and risk of erectile dysfunction—a nationwide population-based surveyPopulation-based survey
between 2000 and 2007, newly diagnosed asthma cases identified (18–55 y) ( )
Control cohort (without asthma) matched for age and co-morbidities ( 13,836)
Cohorts were followed for evidence of erectile dysfunction (ED)Subjects with asthma experienced 1.9-fold increase in ED independent of age and comorbidity compared with control cohortAsthma may be an independent risk factor for ED (increasing with asthma severity)
Chronic systemic inflammation is implicated in this linkage
Dixon, 2012
Expert Reviews in Respiratory Medicine [46]
The treatment of asthma in obesityExpert reviewEpidemiology of obesity has influenced epidemiology of other conditions, for example, asthma
Obesity major risk factor for new asthma
Search strategy not specified
Mechanical factors, metabolic inflammation, and other comorbidities probably contribute to asthmaTherapies need to be developed and tailored to various underlying mechanisms
Juel et al., 2012
Journal of Asthma and Allergy [47]
Asthma and obesity: does weight loss improve asthma control? A systematic reviewSystematic reviewObesity associated with high asthma incidence and poor control
Review of knowledge on effect of weight reduction on asthma control based on systematic searches using the PubMed database and relevant MeSH terms
Weight loss in obese individuals associated with 48%–100% remission of asthma symptoms
Weight loss associated with improved lung function and airway responsiveness to inhaled methacholine
Weight loss consistently reduces asthma symptoms
Improved asthma control including objective measures of disease activity

Atherosclerosis

Gu et al., 2012
Atherosclerosis [48]
Psychological stress, immune response, and atherosclerosisReviewSynthesis of evidences that various immunological factors are transformed under prolonged psychological stress by causing vascular low-grade inflammationEvidence supports expression of pro- and anti-inflammatory cytokines by stress hormones (catecholamines and corticosteroids)Elucidation of two-way communication between neuroendocrine and immune systems Implications for targeted treatment strategies
Kucharz, 2012
Medical Hypotheses [49]
Chronic inflammation-enhanced atherosclerosis: can we consider it a new clinical syndrome?Narrative review
Medical hypothesis:
incidence of cardiovascular disease (CVD) in patients with chronic autoimmune disorders is much higher than in general population
CVD is caused by accelerated atherosclerosis, in which chronic inflammation is implicated
The literature search strategies unspecifiedChronic inflammation-enhanced atherosclerosis syndrome is proposed as a separate syndrome occurring in patients suffering of chronic inflammationAtherosclerosis as an inflammatory disease and chronic extravascular inflammation have common mechanisms resulting in an increase in atherosclerosis and its sequelae, CVD
Lu et al., 2012
Psychosomatic Medicine [50]
Unpredictable chronic mild stress promotes atherosclerosis in high cholesterol-fed rabbitsExperimentalChronic psychological stress associated increased with risk of atherosclerosis
Study of effects of chronic stress on atherogenesis in rabbits
Rabbits fed cholesterol-rich diet for 4–16 wks
High-cholesterol feeding resulted in hypercholesterolemia and formation of atherosclerotic plaques in the aorta
High-cholesterol diet increased plaque size and instability
Findings support that atherosclerosis is augmented by chronic psychological stress, due to increased vascular inflammation and decreased endothelial nitric oxide bioavailability
Ortega et al., 2012
Atherosclerosis [51]
White blood cell count is associated with carotid and femoral atherosclerosisClinical study
Subjects with dyslipidemia ( ) and sex-matched normolipidemic subjects ( )
Examined the association between inflammatory markers and atherosclerosis evidence
Carotid and femoral arteries were imaged
White blood cell counts (WBCC) were obtained
Chronic low-grade inflammation is associated with atherosclerosis
WBCC associated with measures of atherosclerosis independent of risk factors
WBCC is a useful and easy marker of atherosclerosis, consistent with its inflammatory basis
Pinto et al., 2012
Current Pharmaceutical Design [52]
Effects of physical exercise on inflammatory markers of atherosclerosisExpert narrative reviewSynthesis of research related to regular physical training and low-grade
inflammation
Search strategy unspecified
Physical exercise could be considered a useful weapon against local vascular and
systemic inflammation in atherosclerosis.
Several mechanisms explain the positive effect of chronic exercise
Including decreased inflammation and endothelial dysfunction, and modulated progression of underlying disease progress

Cancer

Correa and Piazuelo, 2012 [53]The gastric precancerous cascadeLead article
State-of-the-art
Review of experimental articles that support the steps in the gastric precancerous cascade
Search strategy unspecified
Inflammatory changes may persist throughout the precancerous process
First recognized histological change is active chronic inflammation which is the first step in the precancerous cascade
Most promising strategy for control of the condition is prevention, augmented by prolonging the pre-cancerous process which requires an understanding of the precancerous cascade
Lesion detected earliest in inflammation
Peters et al. 2012
Stress [54]
Chronic psychosocial stress increases the risk for inflammation-related colon carcinogenesis in male mice
Experimental
Animal model
Investigated the effects of chronic psychosocial stress in male mice with artificially induced colorectal cancer (CRC)
Outcomes based on colonoscopic evaluation and protein analysis CSC mice showed accelerated macroscopic lesions
CSC mice showed more cell dysplasia than the single-housed control (SHC) mice
Abnormal protein expression was also greater in CSC than SHC mice
Findings consistent with the fact that chronic psychosocial stress increases the likelihood of developing an irritable bowel, and multiple types of malignant neoplasms, including CRC

Chronic obstructive lung disease

Cox jr 2012
Dose Response [55]
Dose-response thresholds for progressive diseasesNarrative review
To provide evidence base for framework
Framework proposed for understanding how exposure can destabilize normally homeostatic
feedback control systems and create sustained imbalances and elevated levels of disease-related
The resulting model, called the alternative equilibria (AE) theory, implies the existence of an exposure threshold below which transition to the
alternative equilibrium (potential disease)
These predictions may help to explain patterns observed in experimental and epidemiological
data for diseases such as COPD, silicosis, and inflammation-mediated lung cancer
variables,
by creating a new, locally stable, alternative equilibrium for the dynamic system, in addition to its normal (homeostatic) equilibrium
Search strategy unspecified
state will not occur, and once exceeded,
progression to the alternative equilibrium continues spontaneously, even without further exposure
Lindberg et al., 2011
COPD [56]
Co-morbidity in mild-to-moderate COPD: comparison to normal and restrictive lung functionClinical trial
Subjects with COPD from obstructive lung disease in northern Sweden cohort followed in 2002–2004
( )
Gender and age matched reference subjects without COPD
( )
To evaluate if conditions associated with systemic inflammation (e.g., cardiovascular diseases, diabetes, chronic rhinitis, and gastroesophageal reflux, are overrepresented in patients with COPD
Analysis based on interview data on co-morbidity and symptoms
Prevalence of chronic rhinitis and gastroesophageal reflux (GERD) was higher in COPD compared to reference group
In restrictive lung function, the prevalence of chronic rhinitis, cardiovascular disease, hyperlipemia, and diabetes was higher compared to reference group
In COPD and heart disease, chronic rhinitis and/or GERD were proportionately higher than reference group
Co-morbid conditions associated with systemic inflammation, for example, cardiovascular disease, chronic rhinitis, and gastroesophageal reflux, were common in patients with COPD
Overlap between heart disease, chronic rhinitis and GERD was large in COPD
ten Hacken, 2009
Proceeding of the American Thoracic Society [57]
Physical inactivity and obesity: relation to asthma and chronic obstructive pulmonary disease?
Review
To summarize the available literature
regarding the potential role of physical inactivity and obesity in asthma and COPD and to examine their contribution to systemic inflammation
Physical inactivity and obesity are associated with low-grade systemic inflammation that may contribute to the inflammatory processes present in many chronic diseases
Search strategy unspecified
High prevalence of asthma in obesity
In chronic obstructive pulmonary disease (COPD), physical inactivity has been demonstrated
This was associated with a higher degree of systemic inflammation,
Elucidation of the independent relationship between physical inactivity and obesity with systemic inflammation, performance-based studies of physical inactivity in asthma and COPD are needed
independent of body mass index Obesity is associated with the chronic obstructive phenotype and features of the metabolic syndrome
Wouters et al., 2009
Proceedings of the American Thoracic Society [58]
Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection?Review
State-of-the-art
To examine the association between asthma and chronic obstructive pulmonary disease (COPD)
Search strategy unspecified
Spillover of inflammatory mediators into the circulation considered the source of systemic inflammation in these conditions
Nature of systemic inflammation remains unclear
Adipose tissue mediated inflammation is one explanation

Diabetes mellitus (types 1 and 2)

Chang et al., 2012 in press 
Acta Diabetologica [59]
Acute and chronic fluctuations in blood glucose levels can increase oxidative stress in type 2 diabetes mellitus
Clinical trial
Subjects: patients with type 2 diabetes mellitus ( )
To examine whether short- or long-term glycemic fluctuations could induce oxidative stress and chronic inflammation, relationships between glycemic variability, oxidative stress markers, and high-sensitivity C-reactive protein (hs-CRP) were studied
Relationships between markers for short- and long-term glycemic control remained significant with respect to oxidative stress and chronic inflammation, after adjusting for other markers of diabetic control Both acute and chronic blood glucose variability can induce oxidative stress and chronic inflammation
van Bussel et al., 2012 in pressNutrition and Metabolism in Cardiovascular Disease [60]Unhealthy dietary patterns associated with inflammation and endothelial dysfunction in type 1 diabetes: The EURODIAB study
Clinical trial
To investigate the association between nutrient consumption and biomarkers of endothelial dysfunction (ED) and low-grade inflammation (LGI) in subjects with type 1 diabetes ( )
A healthy diet has been inversely associated with ED and LGI
Nutrient consumption and lifestyle risk factors were measured in 1989 and 1997
Biomarkers of ED and LGI (C-reactive protein, interleukin 6, and tumour necrosis factor α) were measured in
Consumption of less fibre, polyunsaturated fat and vegetable protein, and more cholesterol over the study period was associated with more ED and LGIFollowing dietary guidelines in type 1 diabetes may reduce cardiovascular disease risk by favourably affecting ED and LGI
1997 and averaged into -scores. The nutrient residual method was used to adjust individual nutrient intake for energy intake

Fibromyalgia

Kadetoff et al., 2012
Journal of Neuroimmunology [61]
Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels
Clinical trial
Subjects: patients with FM
To assess intrathecal concentrations of pro-inflammatory substances in patients with FMElevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patientsFindings consistent with a central pro-inflammatory component
Ortega et al. 2012
Journal of Medical Science and Sports [62]
Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in patients with fibromyalgia (FM)
Clinical trial
Subjects: women patients with FM and age-matched control group of healthy women
Evaluated the effect of a pool-aquatic exercise program (8 months, two weekly 60 min sessions) on the inflammatory cytokine production by isolated monocytes, and on the serum concentration of C-reactive protein (CRP)Monocytes from FM patients released more inflammatory cytokines than those from women in control group
FM women had high circulating concentrations of CRP Increased IL-6 with a concomitant decreased TNFα spontaneous release was found after 4 months
Anti-inflammatory effect of the exercise program was also corroborated by a decrease in the circulating CRP concentration
FM is associated with chronic inflammation that can be offset with physical exercise such as aquatic exercise
Exercise also improved the health-related quality of life of the FM patients

Hypertension

Berni et al., 2012 
Journal of Human Hypertension [63]
Renal resistive index and low-grade inflammation in patients with essential hypertension
Clinical trial
Subjects: hypertensive patients ( ; 57 ± 14 years, 61 males)
without diabetes, renal
To study the relationship between RRI and serum hsCRP in hypertensives with preserved renal function, without Patients with pathologic RRI ( ) were older and had higher hsCRP levels compared with patients with normal RRI, as well as patients HsCRP is a predictor of both pathologic RRI and decreased RV/RRI, even after adjustment
In essential hypertension,
failure, microalbuminuria, or major inflammatory diseasemicroalbuminuriawith decreased RV/RRI ( )
HsCRP was directly related with RRI and inversely with RV/RRI
low-grade inflammation is associated with tubulointerstitial damage
He et al., 2012
Journal of Hypertension [64]
Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trialRandomized, double-blind, placebo-controlled trial
Subjects: participants randomized to metformin ( ) and participants randomized to placebo ( )
To explore whether metformin-based treatment (which reduces weight and inflammation in diabetes) benefits obesity-related hypertension without diabetes
24 week drug trial
Metformin compared with placebo did not have effects on blood pressure, blood glucose, and high-density or low-density lipoprotein cholesterol, but it did reduce total serum cholesterol
Metformin reduced weight, BMI, waist circumference and both subcutaneous and visceral adiposity and lowered serum high-sensitivity C-reactive protein
Results supported an inflammatory component of hypertension in patient who are obese, that was amenable to metformin that targets inflammation
Sari et al. 2011
Clinical Experimental Hypetension [65]
The effect of quinapril treatment on insulin resistance, leptin and high sensitive C-reactive protein in hypertensive patientsClinical trial
Subjects: hypertensive patients ( ) and control subjects ( )
To evaluate the effect of quinapril on HOMA-IR, high sensitive C-reactive protein, and leptin
Blood pressure, leptin, high sensitive C-reactive protein, and HOMA-IR were determined at baseline and after 3 months of quinapril treatment
After treatment with quinapril HOMA-IR, high sensitive C-reactive protein, and leptin were decreased in hypertensive patientsQuinapril may be used as a therapy for improving blood pressure as well as the insulin resistant, hyperleptinemic, and low-grade inflammatory state in hypertension
Sugiura et al. 2011
Journal of Clinical Lipidology [66]
Impact of lipid profile and high blood pressure on endothelial damage Clinical trial
Japanese male outpatients with grade I or II hypertension,
Blood was sampled for laboratory analysis and endothelialTotal cholesterol to high-density lipoprotein cholesterol ratio Impaired endothelial function was associated with increased
along with gender and age-matched normotensive subjects (both = 25)function was assessed by flow-mediated dilation (FMD)
(total-C/HDL-C) was inversely correlated with the FMD value and positively correlated with both malondialdehyde-modified low-density lipoprotein and high-sensitivity C-reactive protein values
to those in normotensive subjects with high total-C/HDL-C
total-C/HDL-C values, possibly as a result of increased vascular oxidative stress and inflammation
In early stages of atherosclerosis, the impact of both total-C/HDL-C and BP may be similar in terms of endothelial damage

Insulin resistance/metabolic syndrome

Piya et al., 2006 in press 
Journal of Endocrinology [67]
Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxinReviewTo examine impact of nutrients such as glucose and lipids on inflammatory pathways, specifically within adipose tissue, and how these influence adipokine inflammation and insulin resistance
Search strategy unspecified
Through overnutrition, glucose, lipids, and endotoxin affect different tissues to mediate an aberrant inflammatory response and augment pathogenesis of insulin resistance and metabolic diseaseEvidence supports the persistent insults from dysfunctional diets that need to be the targets of intervention
Reducing the burden in this way may impact people’s long-term health
Shoelson et al., 2006
Journal of Clinical Investigation [68]
Inflammation and insulin resistanceReviewEvidence has linked inflammation to the pathogenesis of type 2 diabetes (T2D)
Search strategy unspecified
With discovery of an important role for tissue macrophages, these findings are helping to reshape thinking about how obesity increases the risk for T2D and metabolic syndromeThe evolving concept of insulin resistance and T2D as having immunological components and as improving the picture of how inflammation modulates metabolism provides new opportunities for using anti-inflammatory strategies to address metabolic consequences of excess adiposity

Ischemic heart disease

Simon, 2012
Circulation Journal [69]
Inflammation and vascular injuryReview
To examine the
central role of inflammation in vascular injury and repair
Search strategy unspecified
Binding site for GPIbαin Mac-1 shows that leukocyte engagement of platelet GPIbαvia Mac-1is critical for the biological response to vascular injury, thrombosis, vasculitis, glomerulonephritis, and multiple sclerosisAlmost all inflammation is platelet dependent
Ligand engagement of Mac-1 initiates a novel gene that promotes inflammation
Kalogeropoulos et al., 2012  
Heart Failure Clinics [70]
From risk factors to structural heart disease: the role of inflammationReviewReview strategy unspecifiedElevated levels of circulating proinflammatory cytokines and adipokines have been repeatedly associated with increased risk for clinically manifest (Stage C) heart failure in large cohort studies. The role of low-grade, subclinical inflammatory activity in the transition from risk factors (Stage A heart failure) to structural heart disease (Stage B heart failure) is less well understood
Recent evidence suggests that chronic low-grade inflammatory activity is involved in most mechanisms underlying progression of structural heart disease, including ventricular remodeling after ischemic injury, response to pressure and volume overload, and myocardial fibrosis
Inflammation also contributes to progression of peripheral vascular changes
Vizzardi et al. 2011
Panminerva Medica [71]
Helicobactor pylori and ischemic heart diseaseReviewMany studies have been performed on the relationship between infection from Helicobacter pylori and atherosclerotic diseases, like stroke and ischemic heart disease Review of the literature that has investigated the role of HP in the development and pathogenesis of CAD. Infection could lead to IHD through pathways such as endothelial cells Results from these studies have raised new perspectives on coronary heart disease, especially regarding the possibility of modifying the clinical history of the disease through eradication of these
Some infections could have a role on the genesis and development of damage to the vascular wall and of atheromatous plaque HP could influence the development of IHD through various pathways
Search strategy unspecified
colonization, changes in the lipid profiles, increased coagulation and platelet aggregation levels, induction of molecular mimicry mechanisms, and the promotion of a low-grade systemic inflammationinfective microorganisms
Further studies indicated

Kidney disease

Kang et al., 2012
Journal of Korean Medical Science [72]
Low-grade inflammation, metabolic syndrome and the risk of chronic kidney disease: a 2005 Korean National Health and Nutrition Examination SurveyCross-sectional study
Subjects: adults registered in the national survey ( )
To examine the relationship between white blood cell (WBC) count and chronic kidney disease ≥stage 3
Measures of glomerular filtration rates
Low-grade inflammation is associated with chronic kidney disease in people with metabolic syndrome ≥stage 3Low-grade inflammation associated with chronic kidney disease ≥stage 3 in people with metabolic syndrome suggests new treatment approaches
Kocyigit et al., 2012
American Journal of Nephrology [73]
Early arterial stiffness and inflammatory bio-markers in normotensive polycystic kidney disease patientsClinical trial
Cross-sectional design
Patients ( ) with autosomal-dominant kidney disease (ADPKD) (42% males, 36.6 ± 9.9 years, no blood pressure medication) and healthy controls ( ) (44% males, 35.4 ± 6.4 years)
To clarify temporal relationship between ADPKD, hypertension, and the loss of renal function, patients with early-stage ADPKD who did not yet have hypertension were examined
Pulse wave velocity (PWV), cardiac morphology and function, aortic elastic indexes, estimated glomerular filtration rate (eGFR), 24-hour ambulatory blood pressure, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and highly sensitive C-reactive protein (hs-CRP) were measured
Despite normal blood pressure, aortic stiffness index and pulse wave velocity values were increased in patients compared to controls
In univariate analysis, IL-6, TNF-α, hs-CRP, and eGFR were correlated with PWV PWV is predicted by IL-6, TNF-α, and hs-CRP
Increased arterial stiffness and pulse wave velocity are early manifestations of ADPKD appearing before hypertension or reduced eGFR
These vascular abnormalities are related to signs of systemic low grade inflammation
Findings support a common pathophysiological mechanism apparently present also in other vascular diseases
Luis- Rodríguez et al., 2012
World Journal of Diabetes [74]
Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy
Review (experimental and clinical studies)To identify pathogenic pathways for earlier diagnosis and targeting novel treatments
Search strategy unspecified
Activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy
Experimental and clinical studies support various inflammatory molecules and pathways in the pathoetiology of diabetic neuropathy
Increased knowledge and understanding of inflammatory mechanisms are needed to augment clinical interventions for this complication
Tang et al., 2012
International Journal of Nephrology [75]
Inflammation and oxidative stress in obesity-related glomerulopathyReviewTo focus on inflammation and oxidative stress in the progression of obesity-related glomerulopathy and possible interventions to prevent kidney injury in obesity
Search strategy unspecified
Obesity-related glomerulopathy is a major cause of end-stage renal disease.
Obesity has been considered a state of chronic low-grade systemic inflammation and chronic oxidative stress
Augmented inflammation in adipose and kidney tissues promotes the progression of kidney damage in obesity
Adipose tissue, which is accumulated in obesity, is a key endocrine organ that produces multiple biologically active molecules, including leptin, adiponectin, and resistin, that affect inflammation
Oxidative stress is also associated with obesity-related renal diseases and may trigger the initiation or progression of renal damage in obesity
Both inflammation and oxidative stress induce damage to renal tubule and glomerulus and result in endothelial dysfunction in the kidney
Anti-inflammation and antioxidant
interventions may be therapies to prevent and
treat obesity-related renal diseases

Obesity

Hulsmans et al., 2012
PLoS One [76]
Interleukin-1 receptor-associated kinase-3 is a key inhibitor of inflammation in obesity and metabolic syndrome
Experimental and clinical studies
Obese individuals ( and 102) and age-matched controls ( )
Cluster of molecules were studied that support interactions between the stress conditions of low-grade inflammation and oxidative stress in monocytes
Effect of three month weight loss after bariatric surgery examined
Visceral obesity is associated with type 2 diabetes and metabolic syndrome
Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders
Odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3
Weight loss was with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components
An increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 was identified as the cause of the decrease in IRAK3 in THP-1 cells in vitro
Issa and Griffin, 2012
Pathobiology of Aging and Age Related Diseases [8]
Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammationReviewSearch strategy unspecifiedPathobiology of obesity and osteoarthritis (OA) was examined, as well as literature the underlying systemic inflammation, its relationship to inactivity, and their interactions
Inflammation is central to progression of the disease cycle involving obesity, osteoarthritis, and physical inactivity
Metabolic inflammation is believed to contribute to metabolic inflexibility and on-going production of pro-inflammatory mediators
Findings support that metabolic inflammation increases OA risk
Rico-Rosillo and Vega-Robledo, 2012
Revista Médica del Instituto Mexicano del Seguro Social [77]
New trends in macrophages, inflammation and adipose tissueReviewTo highlight the macrophage participation in the generation of obesity-induced inflammation
Search strategy unspecified
Accumulating evidence suggest the involvement of adipose tissue derived proteins, collectively known as adipokines as well as other factors produced in this tissue by cells besides adipocytes, like fibroblasts, lymphocytes, and macrophages
Obesity burden on health extends across multiple organs systems and diseases (atherosclerosis, coronary heart diseases, osteoarthritis, diabetes, hypertension, and dyslipidemia)
Obesity is considered a low-inflammatory condition
An increasing number of reports suggest that the adipose tissue itself might be a source of pro-inflammatory factors and a target of inflammatory processes
Evidence supports involvement of adipose tissue-derived proteins, collectively known as adipokines and other factors produced in this tissue by cells besides adipocytes (fibroblasts, lymphocytes, and macrophages)
Stienstra, 2007
PPAR Research [78]
PPARs, obesity, and inflammationReviewTo address the role of peroxisome proliferator-activator receptors (PPARs) in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall
Search strategy unspecified
Changes in inflammatory status of adipose tissue and liver with obesity supports co-existent chronic low-level inflammation Various molecular mechanisms have been implicated in obesity-induced inflammation (some modulated by PPARs)
PPARs modulate the inflammatory response, hence, constitute a therapeutic target to mitigate obesity-induced inflammation and its consequences
Obesity is accompanied with fat storage in tissues other than adipose tissue (liver and skeletal muscle) which may lead to local insulin resistance and stimulate inflammation
Obesity changes the morphology and composition of adipose tissue, leading to changes in its protein production and secretion including pro-inflammatory mediators
Tajik et al. 2012 in press 
Journal of Endocrinological Investigation [79]
Effect of diet-induced weight loss on inflammatory cytokines in obese womenClinical trial
Subjects: Premenopausal obese women (body mass index ≥ 30) aged 21 to 54 years without diabetes, hypertension, or hyperlipidemia ( )
To evaluate changes in pro/anti-inflammatory adipocytokines and metabolic profile after moderate diet-induced weight, anthropometric parameters, lipid and glucose profiles, IL-6, IL-10, and IL-18 were measured
Subjects then entered into a weight reduction program (3 months)
Body mass index, waist circumference, triceps skinfold thickness, total cholesterol, triglyceride, and fasting plasma glucose decreased, while HDL-cholesterol increased
While plasma levels of IL-6 and IL-18 decreased, no change was observed in circulating levels of IL-10
Obesity is associated with low-grade systemic inflammation which has been linked to the increased risk of cardiovascular disease and type II diabetes in obese patients
improved body composition induced by restriction of energy intake is associated with favorable serum concentrations of IL-6 and IL-18 in obese women

Rheumatoid arthritis

Gremese and Ferraccioli 2011
Autoimmunology Review [80]
The metabolic syndrome: the crossroads between rheumatoid arthritis and cardiovascular riskReviewRheumatoid arthritis (RA) patients have an incidence of cardiovascular (CV) diseases two-fold that of the general population Atherosclerosis, the main determinant of CV morbidity and mortality, and carotid intima-media thickness, an early preclinical marker of atherosclerosis, also occur early on in RA
Search strategy unspecified
CV risk factors seem to have the same prevalence in RA and non-RA patients, thus they do not fully explain increased CV burden, suggesting that RA inflammation and therapies play a role in increasing CV risk in these patients
The metabolic syndrome (MetS) and fat tissue are likely major players in this complex network
The association of MetS and atherosclerosis is partly mediated by altered secretion of adipokines by adipose tissue and,
Obesity is now regarded as a systemic, low-grade inflammatory state, and inflammation as a link between obesity, metabolic syndrome, and CV diseases
To control CV risk, data support the necessity of “tight control” of inflammation from both RA and MetS
on the other hand, there are evidence that adipokines may play a role in inflammatory RA
Prete et al., 2011
Autoimmunology Review [81]
Extra-articular manifestations of rheumatoid arthritis: An updateReview
Rheumatoid arthritis (RA) is an immune-mediated disease involving chronic low-grade inflammation that may progressively lead to joint destruction, deformity, disability, and even death
Despite its predominant osteoarticular and periarticular manifestations, RA is a systemic disease often associated with cutaneous and organ-specific extra-articular manifestations (EAM)
Current Reviews knowledge about EAM in terms of frequency, clinical aspects, and current therapeutic approaches. In an initial attempt at a classification, we separated EAM from RA co-morbidities and from general, constitutional manifestations of systemic inflammation. EAM was classified as cutaneous and visceral forms, both severe and not severe
Search strategy unspecified
In aggregated data from 12 large RA cohorts, patients with EAM, especially the severe forms, were found to have greater co-morbidity and mortality than patients without EAMUnderstanding the complexity of EAM and their management remains a challenge for clinicians, especially since the effectiveness of drug therapy on EAM awaits study

Stroke

Denes et al. 2011
Cerebrovascular Disease [82]
Interleukin-1 and stroke: biomarker, harbinger of damage, and therapeutic targetReviewInflammation is established as a contributor to cerebrovascular disease
Risk factors for stroke include many conditions associated with chronic or acute inflammation, and inflammatory changes in the brain after cerebrovascular events contribute
Evidence supports importance of peripherally-derived immune cells and inflammatory molecules in various central nervous system disorders, including stroke
Inflammatory cytokine, interleukin-1 (IL-1), plays a pivotal role in both local and systemic
Blockade of IL-1 could be therapeutically useful in several diseases which are risk factors for stroke
There is considerable preclinical and clinical evidence that inhibition of IL-1 by IL-1 receptor antagonist may be valuable in the management of acute stroke
to outcome in experimental studies, with growing evidence from clinical research
Search strategy unspecified
inflammation and is a key driver of peripheral and central immune responses to infection or injury
Wu et al., 2012
American Journal of Rhinological Allergy [83]
Risk of stroke among patients with rhinosinusitis: a population-based study in TaiwanPopulation-based trial
Prospective cohort study
Patients in Taiwan (Longitudinal Health Insurance Database 2005 (LHID2005)) who had received a diagnosis of rhinosinusitis ( 53,653) between January 1, 2004 and December 31, 2005
Control group (1 : 4) drawn from the same database was matched for age and gender ( 214,624)
Each patient was followed up using data entered until the end of 2006
Proportional hazard regressions were performed to evaluate the hazard ratios (HRs) after adjusting for potential confounding factors
Patients with rhinosinusitis were more likely to suffer strokes than the control population, after adjusting for potential confounders
Both acute and chronic sinusitis are risk factors or markers for stroke that is independent of traditional stroke risk factors
Further epidemiological research is warranted