Chronic Low-Grade Inflammation Associated With Osteoarthritis

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Hindawi Publishing CorporationArthritisVolume 2012, Article ID 560634, 28 pagesdoi:10.1155/2012/560634

Review ArticlePrescribing Optimal Nutrition and Physical Activity asFirst-Line Interventions for Best Practice Management ofChronic Low-Grade Inflammation Associated with Osteoarthritis:Evidence Synthesis

Elizabeth Dean1 and Rasmus Gormsen Hansen2

1

Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z32 Department of Physical Therapy, Ringsted and Slagelse Hospitals, Region Zealand, Denmark

Correspondence should be addressed to Elizabeth Dean, [email protected]

Received 7 August 2012; Revised 23 November 2012; Accepted 24 November 2012

Academic Editor: Pierre Youinou

Copyright 2012 E. Dean and R. Gormsen Hansen. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Low-grade inflammation and oxidative stress underlie chronic osteoarthritis. Although best-practice guidelines for osteoarthritisemphasize self-management including weight control and exercise, the role of lifestyle behavior change to address chronic low-grade inflammation has not been a focus of first-line management. This paper synthesizes the literature that supports the idea

in which the Western diet and inactivity are proinflammatory, whereas a plant-based diet and activity are anti-inflammatory,and that low-grade inflammation and oxidative stress underlying osteoarthritis often coexist with lifestyle-related risk factorsand conditions. We provide evidence-informed recommendations on how lifestyle behavior change can be integrated into first-line osteoarthritis management through teamwork and targeted evidence-based interventions. Healthy living can be exploited toreduce inflammation, oxidative stress, and related pain and disability and improve patients overall health. This approach alignswith evidence-based best practice and holds the promise of eliminating or reducing chronic low-grade inflammation, attenuatingdisease progression, reducing weight, maximizing health by minimizing a patients risk or manifestations of other lifestyle-relatedconditions hallmarked by chronic low-grade inflammation, and reducing the need for medications and surgery. This approachprovides an informed cost effective basis for prevention, potential reversal, and management of signs and symptoms of chronicosteoarthritis and has implications for research paradigms in osteoarthritis.

1. Introduction

Best practice guidelines for chronic osteoarthritis focuson self-management, that is, weight control and physical

activity, and on pharmacological support for inflammationand pain [15]. Despite such guidelines, authorities in thefield report a lack of efficacy of current treatments andassociated adverse effects [6], with some proposing evengreater attention to self-management [7]. Further, althoughlow-grade inflammation underlies chronic osteoarthritiscomparable to other conditions with significant lifestyle-related components often presenting concurrently withosteoarthritis, this inflammation has not been a focus of

best practice guidelines, particularly of its nonpharmacologicmanagement.

To establish the prescription of optimal nutrition andphysical activity as first-line interventions for low-gradeinflammation associated with chronic osteoarthritis, we havesynthesized three primary lines of support: (1) the literaturethat supports that the western diet and inactive lifestyle areproinflammatory, and a plant-based diet and regular physicalactivity are anti-inflammatory; (2) the literature supportingthat low-grade inflammation is common across lifestyle-related conditions including osteoarthritis; and (3) evidence-informed recommendations for effecting lifestyle behaviorchange that can be readily integrated by health practitioners


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into first-line management. We conclude with implicationsfor clinical practice and research with respect to its paradigmand avenues for future investigation.

2. Low-Grade Inflammation and Lifestyle

Human lifestyles have changed dramatically over millennia.With technological and economic advancements in westerncountries particularly over the past 60 years, lifestyle-relatedconditions are the leading causes of premature death [13].With globalization, western diets coupled with inactivityhave contributed largely to lifestyle-related conditions whichare increasingly prevalent in middle- and low-income coun-tries [14]. Some authorities have not only argued that west-ern diets have contributed to poor chronic health outcomes,but that national food guidelines such as those in the UnitedStates have legitimized poor nutrition for several decadesfurther contributing to the pandemic of lifestyle-relatedconditions [15]. In particular, poor nutritional quality hasbeen reported to contribute to obesity [16], a primary riskfactor for osteoarthritis [17], in addition to calorie density.

The factors associated with the typical western lifestylethat impact peoples health have been elucidated by cross-cultural studies including seminal work related to Mediter-ranean diet and exercise patterns and Asian lifestyles. TheMediterranean diet known to be health protective is largelyplant based, favors olive oil over animal fats, and is highin fiber, vegetables, and fruits [18]. The China study [1922] is a prime example. This comprehensive series ofstudies has shown the serious health consequences of highconsumption of meat, dairy, fat, and refined grains andsugar (proinflammatory), and low consumption of wholegrains, vegetables and fruits, and legumes and pulses (anti-inflammatory). This unnatural diet for humans contributesto low-grade systemic inflammation and oxidative tissuestress and irritation, placing the immune system in anoveractive state, a common denominator of conditions withlifestyle components including arthritis [15]. Both high car-bohydrate and high fat consumption contribute to inflam-matory and oxidative stress even in healthy people [23].This effect could accentuate inflammatory conditions suchas lowering the threshold for local inflammation in arthritis.Diet-induced weight loss in people who are overweightreduces chronic low-grade inflammation as evidenced bysignification reduced C-reactive protein, an inflammationbiomarker [24].

In addition, sedentary living and inactivity are hallmarksof western culture. Evidence supports that inactivity is proin-flammatory and augments oxidative stress [25], whereasactivity when not excessive is anti-inflammatory [26, 27].More commonly understood about exercise, however, is thatinactivity weakens muscles and contributes to joint stress,in addition to reducing stimulation of synovial fluid whichcushions the joints and protects the joint spaces [28]. Activityand exercise continue to be primarily recommended andprescribed to people with arthritis to offset these adverseeffects. The anti-inflammatory effects of exercise, however,have been well established, and that for maximal anti-inflammatory benefit, broad-based training needs to include

resistance and aerobic training [26, 27, 29]. Exercise inducedanalgesia [30] and stiffness associated with osteoarthritismay reflect both its anti-inflammatory and mechanicaleffects; however, exercises anti-inflammatory effects are notdiscussed in established practice guidelines [15].In sum,thewestern lifestyle is inherently unhealthy, and lifestyles with

nonwestern diets and greater activity levels are typically asso-ciated with better health outcomes, for example, traditionalAsian and Mediterranean lifestyles [18, 31].

Other lifestyle traits common in western culture arealso known to be proinflammatory. Smoking, for example,remains prevalent despite some success in recent decadesin reducing its prevalence through public health campaigns.The chronic low-grade inflammation associated with smok-ing [32, 33] has been linked with inflammatory states associ-ated with ischemic heart disease [34], rheumatoid arthritis[35], and osteoarthritis [36]. Low-grade inflammation hasbeen associated with chronic sleep deprivation and stress[3740] which are also common in western cultures. Giventhe well-documented link between low-grade inflammationand oxidative stress, and sleep deprivation and stress [41], acase can be made for assessing and addressing these in theinitial assessment and in first-line management of chronicosteoarthritis. In addition, sleep deprivation and stress arecommon arthritic complaints secondary to discomfort andpain, lending further support for assessing sleep and stressin people with chronic osteoarthritis and intervening asindicated.

Thus, prescribing healthy living strategies in general aswell as optimal nutrition (of which weight loss is an addi-tional benefit) and regular physical activity are warranted asbeing first-line interventions in clinical practice guidelinesfor conditions such as osteoarthritis associated with chroniclow-grade inflammation. These conditions are described inthe next section and often coexist as comorbidities in peoplewith osteoarthritis.

3. Low-Grade Inflammation andLifestyle-Related ConditionsIncluding Osteoarthritis

Figure 1 illustrates the interactive relationship amongosteoarthritis, obesity, and physical inactivity. Obesity is anindependent risk factor for osteoarthritis [84]. Althoughthe mechanisms for this association are not completely

understood, biomechanical loading and metabolic inflam-mation associated with excess adipose tissue and lipidsmay have a role. Pain associated with osteoarthritis leadsto increasingly less activity and psychosocial and physicaldisability. Physical inactivity is an independent risk factorfor inflammation due to the reduced expression of sys-temic and cellular anti-inflammatory mediators. Physiologiccyclic loading of cartilage tissue reduces the expression ofproinflammatory mediators and decreases cytokine-inducedextracellular matrix degradation. Physical inactivity reducesdaily energy expenditure thereby promoting weight gain andcontinuation of the cycle. Emerging evidence indicates thatosteoarthritis likely impedes the management of chronic


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Physical inactivity

Altered biomechanics

Joint stiffness

Joint pain

Physical limitations

Energetic imbalance

Proinflammatory

effects of diet

Adipose tissue

inflammatory effectsChronic low-grade

systemic

inflammation

Overweight

Obesity OsteoarthritisPsychosocial disability

Figure 1: Relationships among osteoarthritis, obesity, and physical inactivity and relationship to the etiology of chronic low-grade systemicinflammation. Adapted from [8].

metabolic conditions associated with prolonged negativelifestyle habits such as obesity, type 2 diabetes mellitus, andischemic heart disease, because of its negative impact onphysical activity.

Table 1 shows evidence for chronic low-grade inflam-mation and oxidative stress in people with osteoarthritis.Multiple comorbidities that share comparable underlyingchronic low-grade inflammation and oxidative stress oftencoexist in individuals with chronic osteoarthritis, Examplesof these conditions and synthesis of the evidence appearin Table 2, for example, atherosclerosis, chronic cancer,chronic obstructive lung disease, diabetes, hypertension,insulin resistance and metabolic syndrome, ischemic heartdisease, obesity, and stroke. Almost 20 percent of Americanadults report having physician-diagnosed arthritis, and thisis expected to increase over the next two decades [88].Based on the Behavioral Risk Factor Surveillance Systemand National Health Interview Survey in the United States,individuals with osteoarthritis have a high incidence of otherlifestyle-related conditions with inflammatory componentsthat often present comorbidly with osteoarthritis (see exam-ples in Table 2). Our search strategy used keywords includinglifestyle-related conditions, chronic low-grade or chronicsystemic inflammation. This synthesis of evidence reflectsthe literature indexed in established electronic data bases

(MEDLINE and PubMed) and primarily published over thepast five years. However, in several instances, importantrelated work that was published earlier has been includedin this evidence synthesis. The literature extracted representsa breadth of scholarly paradigms including clinical trials,cross-sectional population-based studies, experimental trialsbased on basic science and models and histological evidence,expert narrative reviews, randomized controlled clinicaltrials, and systematic reviews.

Although the degree to which the typical western lifestyleexplains the prevalence of osteoarthritis is unclear, maxi-mizing healthy living may have the greatest potential forminimizing its risk, its impact, and long-term outcomes

including life-long health and wellbeing compared withinvasive interventions including drugs and surgery and theirrelated sequelae and side effects.

Overweight is now considered a leading condition asso-ciated with marked inflammation followed by arthritis, heartdisease, and type 2 diabetes mellitus [89]. The mechanismwhereby overweight contributes to inflammation is reportedto involve high fat content of the diet [90]. Thus, promotinghealthy weight through healthy nutrition in addition toregular physical activity and exercise is critically important topromote a maximally anti-inflammatory systemic environ-ment to offset low-grade inflammation as well as to achieveweight loss.

4. Integration of Lifestyle BehaviorChange into First-Line Management

For lifestyle behavior change to constitute first-line man-agement as the literature would support, the health careteam overall needs to share this goal and practice inpartnership rather than in the conventional siloed care.The three primary health professions excluding, dentistryand pharmacy, include physicians, nurses, and physicaltherapists. Traditionally, physicians are highly trained in

administration of invasive interventions, that is, drugs andsurgery. Nurses have assumed a role in patient education overthe years along with psychosocial considerations of patientcare. Of the established health professions, physical therapy isthe leading nonpharmacologic profession that is particularlywell positioned to assume such an education role for patientsrelated to healthy lifestyles and exercise [91, 92].

Consistent with the 21st century epidemiological trends,physical therapists are moving toward a model of carebased on health (International Classification of Functioning,Disability and Health) [91, 93], which includes initiatingand supporting behavior change such as optimal nutrition,weight reduction, reduced sedentary activity, and increased


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Table1:Synthesisofevidenceofchroniclow-gradeinflammationbeingassociate

dwithosteoarthritis.

Authors

Title

Evidence

classification

Methods

Findings

Conclusion

Ceciletal.,

2005

TheJournalof

Immunology[9]

Inflammation-

induced

chondr

ocyte

hypertrophyis

drivenbyreceptor

foradvanced

glycatio

nend

produc

ts

Basicsciencestudy

Experimentalstudy

Analysisofhuman

cartilage,cultured

humanarticular

chondrocytes,and

recombinant

humanS100A11,

solubleRAGE

(advanced

glycationend

products),and

RAGE-specific

blocking

antibodies

Normalhuman

kneecartilages

showed

constitutiveRAGE

andS100A11

expression,and

RAGEand

S100A11

expressionwere

upregulatedinOA

cartilages

Up-regulated

chondrocyte

expressioninOA

cartilageand

RAGEsignaling

promote

inflammation-

associated

chondrocyte

hypertrophy

Rojas-Rodrguezet

al.,

2007

Medical

Hypotheses[10]

Therelation

betweenthe

metabo

lic

syndromeand

energy-utilization

deficitinthe

pathogenesisof

obesity-induced

osteoar

thritis

Narrativereview

to

examineamedical

hypothesis:

pathogenesisof

obesity-induced

OAmaybe

explainedby

metabolicchanges

instriatedmuscle

byinteractiono

f

insulinresistance

andsystemic

inflammationin

obeseindividua

ls

Evidencesearch

strategy

unspecified

IncreasedTH1

cytokinesare

producedby

macrophagesin

presenceofchronic

infectionand

suppressinsulin

sensitivity

Musclecellsand

adipocytesare

activatedby

inflammatory

cytokinesand

contributeto

chroniclow-grade

inflammationin

apparentlyhealthy

obeseindividuals

Thefatigueand

muscleweakness

inducedbyinsulin

resistanceand

inflammationin

obesepatientswith

metabolic

syndrome

(pro-inflammatory

state)increase

traumatojoints

thatresultin

breakingof

tenoperiosteal

junctionand

abrasivedamageof

cartilage


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Table1:Continued.

Authors

Title

Evidence

classification

Methods

Findings

Conclusion

Schlesingerand

Thiele,2

010

Annalsof

Rheumatic

Diseases[11]

Thepathogenesis

ofboneerosions

areing

outy

arthritis

Review

Synthesisof

mechanical,

pathological,

cellular,and

immunological

factorsroleinthe

pathogenesisof

boneerosionsin

goutyarthritis

Searchstrategy

unspecified

Monosodiumurate

crystaldeposition

associatedwith

underlyingOA

Goutytophusand

boneerosions

associatedwith

chroniclow-grade

inflammation

Tophuseroding

underlyingboneis

pivotalfor

developmentof

boneerosionsin

goutyarthritis

Smithetal.1

997

Journalof

Rheumatology

[12]

Synovial

membr

ane

inflammationand

cytokin

e

produc

tionin

patientswithearly

osteoar

thritis

Clinicaltrialof

patientswith

varyingstageso

f

earlyOA(n=6

3)

Synovial

membranesamples

obtainedfromthe

kneesofpatients

Thickeningof

lininglayer,

increased

vascularity,and

inflammatorycell

infiltrationin

synovial

membranes;

changes

proportionalto

severity

Inflammatory

markersincreased

inthesynovial

membranesof

patients

irrespectiveof

degreeofarticular

damage

Chronic

inflammatory

changeswith

productionof

pro-inflammatory

cytokines

characterizethe

synovial

membranesof

patientswithearly

OA

Low-grade

synovitisresultsin

theproductionof

cytokinesthatmay

contributetoOA

pathogenesis


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Table2:Continued.

Kucharz,2012

MedicalHypotheses[49]

Chronic

inflammation-enhanced

atheroscle

rosis:canwe

consideritanewclinical

syndrome

?

Narrativereview

Medicalhypothesis:

incidenceof

cardiovasculardiseas

e

(CVD)inpatientswith

chronicautoimmune

disordersismuchhigher

thaningeneral

population

CVDiscausedby

accelerated

atherosclerosis,inwhich

chronicinflammationis

implicated

Theliteraturesearch

strategiesunspecified

Chronic

inflammation-enhanced

atherosclerosis

syndromeisproposedas

aseparatesyndrome

occurringinpatients

sufferingofchronic

inflammation

Atherosclerosisasan

inflammatorydisease

andchronic

extravasc

ular

inflammationhave

common

mechanisms

resulting

inanincrease

inathero

sclerosisandits

sequelae,C

VD

Luetal.,

2012

PsychosomaticMedicine

[50]

Unpredictablechronic

mildstresspromotes

atheroscle

rosisinhigh

cholestero

l-fedrabbits

Experimental

Chronicpsychological

stressassociatedincreased

withriskofatherosclerosis

Studyofeffectsofchronic

stressonatherogenesisin

rabbits

Rabbitsfedcholesterol-rich

dietfor416wks

High-cholesterolfeeding

resultedin

hypercholesterolemia

andformationof

atheroscleroticplaques

intheaorta

High-cholesteroldiet

increasedplaquesize

andinstability

Findings

supportthat

atherosclerosisis

augmentedbychronic

psychologicalstress,due

toincreasedvascular

inflammationand

decreasedendothelial

nitricoxide

bioavailability

Ortegaetal.,

2012

Atherosclerosis[51]

Whiteblo

odcellcountis

associated

withcarotid

andfemoral

atheroscle

rosis

Clinicalstudy

Subjectswith

dyslipidemia(n=55

4)

andsex-matched

normolipidemicsubjects

(n=

246)

Examinedtheassociation

betweeninflammatory

markersandatherosclerosis

evidence

Carotidandfemoral

arterieswereimaged

Whitebloodcellcounts

(WBCC)wereobtained

Chroniclow-grade

inflammationis

associatedwith

atherosclerosis

WBCCassociatedwith

measuresof

atherosclerosis

independentofrisk

factors

WBCCisausefuland

easymarkerof

atherosclerosis,

consisten

twithits

inflammatorybasis

Pintoetal.,

2012

CurrentPharmaceutical

Design[52]

Effectsofphysical

exerciseon

inflammatorymarkers

ofatheros

clerosis

Expertnarrativereview

Synthesisofresearch

relatedtoregularphysical

trainingandlow-grade

inflammation

Searchstrategyunspecified

Physicalexercisecould

beconsideredauseful

weaponagainstlocal

vascularand

systemicinflammation

inatherosclerosis.

Severalm

echanisms

explainthepositive

effectofchronicexercise

Includingdecreased

inflammationand

endothelialdysfunction,

andmod

ulated

progressionof

underlyingdisease

progress


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Table2:Continued.

Cancer

CorreaandPiazuelo,

2012[53]

Thegastricprecancerous

cascade

Leadarticle

State-of-the-art

Reviewofexperimental

articlesthatsupportthe

stepsinthegastric

precancerouscascade


Inflammatorychanges

maypersistthroughout

theprecancerousprocess

Firstrecognized

histologicalchangeis

activechronic

inflammationwhichis

thefirststepinthe

precancerouscascade

Mostpro

misingstrategy

forcontrolofthe

conditionisprevention,

augmentedby

prolongingthe

pre-cancerousprocess

whichrequiresan

understandingofthe

precancerouscascade

Lesiondetectedearliest

ininflam

mation

Petersetal.2

012

Stress[54]

Chronicp

sychosocial

stressincr

easestherisk

forinflam

mation-related

coloncarcinogenesisin

malemice

Experimental

Animalmodel

Investigatedtheeffec

ts

ofchronicpsychosoc

ial

stressinmalemicew

ith

artificiallyinduced

colorectalcancer(CR

C)

Outcomesbasedon

colonoscopicevaluation

andproteinanalysis

CSCmiceshowed

acceleratedmacroscopic

lesions

CSCmiceshowedmore

celldysplasiathanthe

single-housedcontrol

(SHC)mice

Abnormalprotein

expressionwasalso

greaterinCSCthanSHC

mice

Findings

consistentwith

thefactthatchronic

psychoso

cialstress

increases

thelikelihood

ofdevelo

pingan

irritablebowel,and

multiple

typesof

malignan

tneoplasms,

includingCRC

Chronicobstructivelungdisease

Coxjr2012

DoseResponse[55]

Dose-resp

onse

thresholdsfor

progressiv

ediseases

Narrativereview

Toprovideevidencebase

forframework

Frameworkproposedfor

understandinghow

exposurecandestabilize

normallyhomeostatic

feedbackcontrolsystems

andcreatesustained

imbalancesandelevated

levelsofdisease-related

Theresultingmodel,

calledthealternative

equilibria(AE)theory,

impliestheexistenceof

anexposurethreshold

belowwhichtransition

tothe

alternativeequilibrium

(potentialdisease)

Thesepredictionsmay

helptoexplainpatterns

observed

in

experime

ntaland

epidemio

logical

datafordiseasessuchas

COPD,silicosis,and

inflammation-mediated

lungcancer


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Table2:Continued.

variables,

bycreatinganew,locally

stable,a

lternative

equilibriumforthe

dynamicsystem,in

additiontoitsnormal

(homeostatic)equilibrium


statewillnotoccur,and

onceexceeded,

progressiontothe

alternativeequilibrium

continues

spontaneously,even

withoutfurther

exposure

Lindbergetal.,

2011

COPD[56]

Co-morbidityin

mild-to-m

oderate

COPD:co

mparisonto

normalan

drestrictive

lungfunction

Clinicaltrial

SubjectswithCOPD

fromobstructivelung

diseaseinnorthern

Swedencohortfollow

ed

in20022004

(n=

993)

Genderandagematched

referencesubjects

withoutCOPD

(n=

993)

Toevaluateifconditions

associatedwithsystemic

inflammation(e.g.,

cardiovasculardiseases,

diabetes,chronicrhinitis,

andgastroesophageal

reflux,areoverrepresented

inpatientswithCOPD

Analysisbasedoninterview

dataonco-morbidityand

symptoms

Prevalenceofchronic

rhinitisand

gastroesophagealreflux

(GERD)washigherin

COPDcomparedto

referencegroup

Inrestrictivelung

function,t

heprevalence

ofchronicrhinitis,

cardiovasculardisease,

hyperlipemia,and

diabeteswashigher

comparedtoreference

group

InCOPDandheart

disease,c

hronicrhinitis

and/orGERDwere

proportionatelyhigher

thanreferencegroup

Co-morb

idconditions

associatedwithsystemic

inflammation,for

example,cardiovascular

disease,c

hronicrhinitis,

andgastr

oesophageal

reflux,werecommonin

patientswithCOPD

Overlapbetweenheart

disease,c

hronicrhinitis

andGER

Dwaslargein

COPD

tenHacken,2

009

Proceedingofthe

AmericanThoracic

Society[57]

Physicalinactivityand

obesity:relationto

asthmaan

dchronic

obstructiv

epulmonary

disease?

Review

Tosummarizethe

availableliterature

regardingthepotential

roleofphysicalinactivity

andobesityinasthm

a

andCOPDandto

examinetheir

contributiontosystemic

inflammation

Physicalinactivityand

obesityareassociatedwith

low-gradesystemic

inflammationthatmay

contributetothe

inflammatoryprocesses

presentinmanychronic

diseases


Highprevalenceof

asthmainobesity

Inchronicobstructive

pulmonarydisease

(COPD),physical

inactivityhasbeen

demonstrated

Thiswasassociatedwith

ahigherdegreeof

systemicinflammation,

Elucidationofthe

independ

ent

relationshipbetween

physicalinactivityand

obesityw

ithsystemic

inflammation,

performa

nce-based

studiesofphysical

inactivity

inasthmaand

COPDareneeded


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Table2:Continued.

independentofbody

massindexObesityis

associatedwiththe

chronicobstructive

phenotypeandfeatures

ofthemetabolic

syndrome

Woutersetal.,

2009

Proceedingsofthe

AmericanThoracic

Society[58]

Systemicandlocal

inflammationinasthma

andchron

icobstructive

pulmonar

ydisease:is

thereaconnection?

Review

State-of-the-art

Toexaminetheassociation

betweenasthmaand

chronicobstructive

pulmonarydisease

(COPD)


Spilloverof

inflammatorymediators

intothecirculation

consideredthesourceof


intheseconditions

Natureofsystemic

inflammationremains

unclear

Adiposetissuemediated

inflammationisone

explanation

Diabetesmellitus(types1and2)

Changetal.,

2012in

press

ActaDiabetologica[59]

Acuteand

chronic

fluctuationsinblood

glucoselevelscan

increaseo

xidativestress

intype2diabetes

mellitus

Clinicaltrial

Subjects:patientswith

type2diabetesmellitus

(n=

34)

Toexaminewhethershort-

orlong-termglycemic

fluctuationscouldinduce

oxidativestressandchronic

inflammation,

relationshipsbetween

glycemicvariability,

oxidativestressmarkers,

andhigh-sensitivity

C-reactiveprotein

(hs-CRP)werestudied

Relationshipsbetween

markersforshort-and

long-termglycemic

controlremained

significantwithrespect

tooxidativestressand

chronicinflammation,

afteradjustingforother

markersofdiabetic

control

Bothacuteandchronic

bloodglu

cosevariability

caninduceoxidative

stressandchronic

inflammation

vanBusseletal.,

2012in

pressNutritionand

Metabolismin

CardiovascularDisease

[60]

Unhealthydietary

patternsa

ssociatedwith

inflammationand

endothelialdysfunction

intype1diabetes:The

EURODIABstudy

Clinicaltrial

Toinvestigatethe

associationbetween

nutrientconsumptio

n

andbiomarkersof

endothelialdysfunction

(ED)andlow-grade

inflammation(LGI)in

subjectswithtype1

diabetes(n=

491)

Ahealthydiethasbeen

inverselyassociatedwith

EDandLGI

Nutrientconsumptionand

lifestyleriskfactorswere

measuredin1989and1997

BiomarkersofEDandLGI

(C-reactiveprotein,

interleukin6,andtumour

necrosisfactor)were

measuredin

Consumptionofless

fibre,polyunsaturated

fatandvegetable

protein,andmore

cholesteroloverthe

studyperiodwas

associatedwithmoreED

andLGI

Followingdietary

guideline

sintype1

diabetesmayreduce

cardiovasculardisease

riskbyfa

vourably

affecting

EDandLGI


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Table2:Continued.

1997andaveragedinto

Z-scores.Thenutrient

residualmethodwasused

toadjustindividual

nutrientintakeforenergy

intake

Fibromyalgia

Kadetoffetal.,

2012

Journalof

Neuroimmunology[61]

Evidenceofcentral

inflammationin

fibromyalgia-increased

cerebrospinalfluid

interleukin-8levels

Clinicaltrial

Subjects:patientswith

FM

Toassessintrathecal

concentrationsof

pro-inflammatory

substancesinpatientswith

FM

Elevatedcerebrospinal

fluidandserum

concentrationsof

interleukin-8,butnot

interleukin-1beta,inFM

patients

Findings

consistentwith

acentral

pro-inflammatory

compone

nt

Ortegaetal.2

012

JournalofMedical

ScienceandSports[62]

Aquaticexercise

improves

themonocyte

pro-and

anti-inflammatory

cytokinep

roduction

balancein

patientswith

fibromyalgia(FM)

Clinicaltrial

Subjects:women

patientswithFMand

age-matchedcontrol

groupofhealthywom

en

Evaluatedtheeffectofa

pool-aquaticexercise

program(8months,two

weekly60minsessions)on

theinflammatorycytokine

productionbyisolated

monocytes,andonthe

serumconcentrationof

C-reactiveprotein(CRP)

MonocytesfromFM

patientsreleasedmore

inflammatorycytokines

thanthosefromwomen

incontrolgroup

FMwomenhadhigh

circulating

concentrationsofCRP

IncreasedIL-6witha

concomitantdecreased

TNFspontaneous

releasewasfoundafter4

months

Anti-inflammatory

effectoftheexercise

programwasalso

corroboratedbya

decreaseinthe

circulatingCRP

concentration

FMisass

ociatedwith

chronicinflammation

thatcanbeoffsetwith

physicalexercisesuchas

aquaticexercise

Exercisealsoimproved

thehealth-related

qualityoflifeoftheFM

patients

Hypertension

Bernietal.,

2012

JournalofHuman

Hypertension[63]

Renalresistiveindexand

low-grade

inflammation

inpatientswithessential

hypertens

ion

Clinicaltrial

Subjects:hypertensiv

e

patients(n=

85;57

14years,61males)

withoutdiabetes,ren

al

Tostudytherelationship

betweenRRIandserum

hsCRPinhypertensives

withpreservedrenal

function,w

ithout

Patientswithpathologic

RRI(n=

21)wereolder

andhadhigherhsCRP

levelscomparedwith

patientswithnormal

RRI,aswellaspatients

HsCRPisapredictorof

bothpathologicRRIand

decreasedRV/RRI,even

afteradju

stment

Inessential

hypertension,


13/28

Arthritis 13

Table2:Continued.

failure,

microalbuminuria,o

r

majorinflammatory

disease

microalbuminuria

withdecreasedRV/RRI

(n=

43)

HsCRPwasdirectly

relatedwithRRIand

inverselywithRV/RRI

low-grad

einflammation

isassocia

tedwith

tubulointerstitial

damage

Heetal.,

2012

JournalofHypertension

[64]

Metformin-based

treatment

for

obesity-re

lated

hypertens

ion:a

randomized,

double-blind,

placebo-controlledtrial

Randomized,

double-blind,

placebo-controlledtrial

Subjects:participants

randomizedto

metformin(n=

180)

andparticipants

randomizedtoplacebo

(n=

180)

Toexplorewhether

metformin-based

treatment(whichreduces

weightandinflammation

indiabetes)benefits

obesity-related

hypertensionwithout

diabetes

24weekdrugtrial

Metformincompared

withplacebodidnot

haveeffectsonblood

pressure,b

loodglucose,

andhigh-densityor

low-densitylipoprotein

cholesterol,butitdid

reducetotalserum

cholesterol

Metforminreduced

weight,BMI,waist

circumferenceandboth

subcutaneousand

visceraladiposityand

loweredserum

high-sensitivity

C-reactiveprotein

Resultssupportedan

inflammatory

compone

ntof

hypertensioninpatient

whoareobese,thatwas

amenabletometformin

thattargets

inflammation

Sarietal.2

011

ClinicalExperimental

Hypetension[65]

Theeffect

ofquinapril

treatment

oninsulin

resistance,leptinand

highsensitiveC-reactive

proteinin

hypertensive

patients

Clinicaltrial

Subjects:hypertensiv

e

patients(n=

54)and

controlsubjects(n=

24)

Toevaluatetheeffectof

quinaprilonHOMA-IR,


protein,andleptin

Bloodpressure,leptin,h

igh

sensitiveC-reactiveprotein,

andHOMA-IRwere

determinedatbaselineand

after3monthsofquinapril

treatment

Aftertreatmentwith

quinaprilHOMA-IR,


protein,andleptinwere

decreasedin

hypertensivepatients

Quinaprilmaybeused

asathera

pyfor

improvin

gblood

pressureaswellasthe

insulinresistant,

hyperleptinemic,and

low-grad

einflammatory

stateinhypertension

Sugiuraetal.2

011

JournalofClinical

Lipidology[66]

Impactof

lipidprofile

andhighbloodpressure

onendoth

elialdamage

Clinicaltrial

Japanesemale

outpatientswithgradeI

orIIhypertension,

Bloodwassampledfor

laboratoryanalysisand

endothelial

Totalcholesterolto

high-densitylipoprotein

cholesterolratio

Impaired

endothelial

function

wasassociated

withincr

eased


14/28

14 Arthritis

Table2:Continued.

alongwithgenderan

d

age-matched

normotensivesubjects

(bothn=

25)

functionwasassessedby

flow-mediateddilation

(FMD)

(total-C/HDL-C)was

inverselycorrelatedwith

theFMDvalueand

positivelycorrelated

withboth

malondialdehyde-

modifiedlow-density

lipoproteinand

high-sensitivity

C-reactiveproteinvalues

tothoseinnormotensive

subjectswithhigh

total-C/HDL-C

total-C/H

DL-Cvalues,

possiblyasaresultof

increased

vascular

oxidative

stressand

inflammation

Inearlys

tagesof

atherosclerosis,t

he

impactofboth

total-C/H

DL-CandBP

maybesimilarinterms

ofendothelialdamage

Insulinresistance/metabolicsyndrome

Piyaetal.,

2006inpress

Journalof

Endocrinology[67]

Adipokineinflammation

andinsulinresistance:

theroleofglucose,l

ipids

andendotoxin

Review

Toexamineimpactof

nutrientssuchasglucose

andlipidsoninflammatory

pathways,specifically

withinadiposetissue,and

howtheseinfluence

adipokineinflammation

andinsulinresistance


Throughovernutrition,

glucose,l

ipids,and

endotoxinaffect

differenttissuesto

mediateanaberrant

inflammatoryresponse

andaugment

pathogenesisofinsulin

resistanceandmetabolic

disease

Evidence

supportsthe

persistentinsultsfrom

dysfunctionaldietsthat

needtob

ethetargetsof

intervent

ion

Reducing

theburdenin

thiswaymayimpact

peopleslong-term

health

Shoelsonetal.,

2006

JournalofClinical

Investigation[68]

Inflamma

tionand

insulinresistance

Review

Evidencehaslinked

inflammationtothe

pathogenesisoftype2

diabetes(T2D)


Withdiscoveryofan

importantrolefortissue

macrophages,t

hese

findingsarehelpingto

reshapethinkingabout

howobesityincreases

theriskforT2Dand

metabolicsyndrome

Theevolvingconceptof

insulinresistanceand

T2Dashaving

immunological

compone

ntsandas

improvin

gthepictureof

howinfla

mmation

modulatesmetabolism

provides

new

opportun

itiesforusing

anti-infla

mmatory

strategiestoaddress

metabolicconsequences

ofexcess

adiposity


15/28

Arthritis 15

Table2:Continued.

Ischemicheartdisease

Simon,2

012

CirculationJournal[69]

Inflamma

tionand

vascularinjury

Review

Toexaminethe

centralroleof

inflammationinvascular

injuryandrepair


BindingsiteforGPIb

inMac-1showsthat

leukocyteengagementof

plateletGPIbvia

Mac-1iscriticalforthe

biologicalresponseto

vascularinjury,

thrombosis,vasculitis,

glomerulonephritis,and

multiplesclerosis

Almostallinflammation

isplateletdependent

Ligandengagementof

Mac-1in

itiatesanovel

genethatpromotes

inflammation

Kalogeropoulosetal.,

2012

HeartFailureClinics

[70]

Fromrisk

factorsto

structuralheartdisease:

theroleofinflammation

Review

Reviewstrategyunspecified

Elevatedlevelsof

circulating

proinflammatory

cytokinesand

adipokineshavebeen

repeatedlyassociated

withincreasedriskfor

clinicallymanifest(Stage

C)heartfailureinlarge

cohortstudies.Therole

oflow-grade,subclinical

inflammatoryactivityin

thetransitionfromrisk

factors(StageAheart

failure)tostructural

heartdisease(StageB

heartfailure)islesswell

understood

Recentevidencesuggests

thatchro

niclow-grade

inflammatoryactivityis

involved

inmost

mechanismsunderlying

progressionofstructural

heartdisease,including

ventricularremodeling

afterisch

emicinjury,

response

topressureand

volumeo

verload,and

myocardialfibrosis

Inflammationalso

contributesto

progressionof

peripheralvascular

changes

Vizzardietal.2

011

PanminervaMedica[71]

Helicobactorpyloriand

ischemicheartdisease

Review

Manystudieshavebeen

performedonthe

relationshipbetween

infectionfromHelicobacter

pyloriandatherosclerotic

diseases,likestrokeand

ischemicheartdisease

Reviewoftheliterature

thathasinvestigatedthe

roleofHPinthe

developmentand

pathogenesisofCAD.

Infectioncouldleadto

IHDthroughpathways

suchasendothelialcells

Resultsfromthese

studieshaveraisednew

perspectivesoncoronary

heartdisease,especially

regardingthepossibility

ofmodifyingtheclinical

historyofthedisease

througheradicationof

these


16/28

16 Arthritis

Table2:Continued.

Someinfectionscouldhave

aroleonthegenesisand

developmentofdamageto

thevascularwallandof

atheromatousplaqueHP

couldinfluencethe

developmentofIHD

throughvariouspathways


colonization,c

hangesin

thelipidprofiles,

increasedcoagulation

andplateletaggregation

levels,inductionof

molecularmimicry

mechanisms,andthe

promotionofa

low-gradesystemic

inflammation

infective

microorg

anisms

Furthers

tudiesindicated

Kidneydisease

Kangetal.,

2012

JournalofKorean

MedicalScience[72]

Low-grade

inflammation,metabolic

syndrome

andtheriskof

chronickidneydisease:a

2005Kore

anNational

HealthandNutrition

ExaminationSurvey

Cross-sectionalstudy

Subjects:adults

registeredinthenational

survey(n=

5291)

Toexaminetherelationship

betweenwhitebloodcell

(WBC)countandchronic

kidneydiseasestage3

Measuresofglomerular

filtrationrates

Low-grade

inflammationis

associatedwithchronic

kidneydiseaseinpeople

withmetabolic

syndromestage3

Low-grade

inflammationassociated

withchro

nickidney

disease

stage3in

peoplewithmetabolic

syndromesuggestsnew

treatmen

tapproaches

Kocyigitetal.,

2012

AmericanJournalof

Nephrology[73]

Earlyarterialstiffness

andinflam

matory

bio-markersin

normoten

sivepolycystic

kidneydiseasepatients

Clinicaltrial

Cross-sectionaldesig

n

Patients(n=

50)with

autosomal-dominant

kidneydisease(ADPKD)

(42%males,3

6.69

.9

years,nobloodpress

ure

medication)andhealthy

controls(n=

50)(44

%

males,3

5.4

6.4yea

rs)

Toclarifytemporal

relationshipbetween

ADPKD,hypertension,and

thelossofrenalfunction,

patientswithearly-stage

ADPKDwhodidnotyet

havehypertensionwere

examined

Pulsewavevelocity(PWV),

cardiacmorphologyand

function,aorticelastic

indexes,estimated

glomerularfiltrationrate

(eGFR),24-hour

ambulatorybloodpressure,

interleukin-6(IL-6),tumor

necrosisfactor-(TNF-),

andhighlysensitive

C-reactiveprotein

(hs-CRP)weremeasured

Despitenormalblood

pressure,aorticstiffness

indexandpulsewave

velocityvalueswere

increasedinpatients

comparedtocontrols

Inunivariateanalysis,

IL-6,T

NF-,hs-CRP,

andeGFRwere

correlatedwithPWV

PWVispredictedby

IL-6,T

NF-,and

hs-CRP

Increased

arterial

stiffnessandpulsewave

velocitya

reearly

manifestationsof

ADPKDappearing

beforehy

pertensionor

reducedeGFR

Thesevascular

abnorma

litiesarerelated

tosignso

fsystemiclow

gradeinfl

ammation

Findings

supporta

common

pathophysiological

mechanismapparently

presentalsoinother

vasculardiseases


17/28

Arthritis 17

Table2:Continued.

Luis-Rodrguezetal.,

2012

WorldJournalof

Diabetes[74]

Pathophysiologicalrole

andtherapeutic

implicatio

nsof

inflammationindiabetic

nephropathy

Review(experimental

andclinicalstudies)

Toidentifypathogenic

pathwaysforearlier

diagnosisandtargeting

noveltreatments


Activationofinnate

immunitywith

developmentofa

chroniclowgrade

inflammatoryresponse

isarecognizedfactorin

thepathogenesisof

diabeticnephropathy

Experimentaland

clinicalstudiessupport

variousinflammatory

moleculesandpathways

inthepathoetiologyof

diabeticneuropathy

Increased

knowledge

andunderstandingof

inflammatory

mechanismsareneeded

toaugme

ntclinical

intervent

ionsforthis

complica

tion

Tangetal.,

2012

InternationalJournalof

Nephrology[75]

Inflamma

tionand

oxidativestressin

obesity-re

lated

glomerulo

pathy

Review

Tofocusoninflammation

andoxidativestressinthe

progressionof

obesity-related

glomerulopathyand

possibleinterventionsto

preventkidneyinjuryin

obesity


Obesity-related

glomerulopathyisa

majorcauseofend-stage

renaldisease.

Obesityhasbeen

consideredastateof

chroniclow-grade


andchronicoxidative

stress

Augmented

inflammationinadipose

andkidneytissues

promotesthe

progressionofkidney

damageinobesity

Adiposetissue,whichis

accumulatedinobesity,

isakeyendocrineorgan

thatprod

ucesmultiple

biologica

llyactive

molecule

s,including

leptin,ad

iponectin,and

resistin,thataffect

inflammation

Oxidativestressisalso

associatedwith

obesity-relatedrenal

diseasesandmaytrigger

theinitiationor

progressionofrenal

damageinobesity

Bothinflammationand

oxidative

stressinduce

damaget

orenaltubule

andglom

erulusand

resultinendothelial

dysfunctioninthe

kidney

Anti-inflammationand

antioxida

nt


18/28

18 Arthritis

Table2:Continued.

intervent

ionsmaybe

therapies

topreventand

treatobesity-related

renaldiseases

Obesity

Hulsmansetal.,

2012

PLoSOne[76]

Interleukin-1

receptor-associated

kinase-3isakey

inhibitorof

inflammationinobesity

andmetabolicsyndrome

Experimentaland

clinicalstudies

Obeseindividuals

(n=

21and102)and

age-matchedcontrols

(n=

46)

Clusterofmoleculeswere

studiedthatsupport

interactionsbetweenthe

stressconditionsof

low-gradeinflammation

andoxidativestressin

monocytes

Effectofthreemonth

weightlossafterbariatric

surgeryexamined

Visceralobesityis

associatedwithtype2

diabetesandmetabolic

syndrome

Low-gradechronic

inflammationand

oxidativestresssynergize

inobesityand

obesity-induced

disorders

Oddsratioof

high-sensitivity

C-reactiveprotein,a

widelyusedmarkerof


was4.3

Weightlo

sswaswitha

lowering

ofsystemic

inflammationanda

decreasin

gnumberof

metabolicsyndrome

compone

nts

Anincreaseinreactive

oxygenspeciesin

combinationwith

obesity-a

ssociatedlow

adiponec

tinandhigh

glucosea

nd

interleukin-6was

identified

asthecauseof

thedecre

aseinIRAK3in

THP-1cellsinvitro

IssaandGriffin,2

012

PathobiologyofAging

andAgeRelatedDiseases

[8]

Pathobiologyofobesity

andosteoarthritis:

integratin

g

biomechanicsand

inflammation

Review


Pathobiologyofobesity

andosteoarthritis(OA)

wasexamined,aswellas

literaturetheunderlying


itsrelationshipto

inactivity,andtheir

interactions

Inflammationiscentral

toprogre

ssionofthe

diseasecycleinvolving

obesity,o

steoarthritis,

andphysicalinactivity

Metabolicinflammation

isbelievedtocontribute

tometabolicinflexibility

andon-g

oing

productionof

pro-inflammatory

mediator

s

Findings

supportthat

metabolicinflammation

increases

OArisk


19/28

Arthritis 19

Table2:Continued.

Rico-Rosilloand

Vega-Robledo,2012

RevistaMedicadel

InstitutoMexicanodel

SeguroSocial[77]

Newtrendsin

macropha

ges,

inflammationand

adiposetissue

Review

Tohighlightthe

macrophageparticipation

inthegenerationof

obesity-induced

inflammation


Accumulatingevidence

suggesttheinvolvement

ofadiposetissuederived

proteins,collectively

knownasadipokinesas

wellasotherfactors

producedinthistissue

bycellsbesides

adipocytes,like

fibroblasts,lymphocytes,

andmacrophages

Obesityburdenon

healthextendsacross

multipleorganssystems

anddiseases

(atherosclerosis,

coronaryheartdiseases,

osteoarthritis,diabetes,

hypertension,and

dyslipidemia)

Obesityisconsidereda

low-inflammatory

condition

Anincreasingnumberof

reportssuggestthatthe

adiposetissueitself

mightbe

asourceof

pro-inflammatory

factorsandatargetof

inflammatoryprocesses

Evidence

supports

involvem

entofadipose

tissue-derivedproteins,

collective

lyknownas

adipokinesandother

factorsproducedinthis

tissueby

cellsbesides

adipocytes(fibroblasts,

lymphocytes,and

macrophages)

Stienstra,2

007

PPARResearch[78]

PPARs,ob

esity,and

inflammation

Review

Toaddresstheroleof

peroxisome

proliferator-activator

receptors(PPARs)in

obesity-induced

inflammationspecifically

inadiposetissue,liver,and

thevascularwall


Changesin

inflammatorystatusof

adiposetissueandliver

withobesitysupports

co-existentchronic

low-levelinflammation

Variousmolecular

mechanismshavebeen

implicatedin

obesity-induced

inflammation(some

modulatedbyPPARs)

PPARsmodulatethe

inflammatoryresponse,

hence,constitutea

therapeutictargetto

mitigateobesity-induced

inflammationandits

consequences

Obesityisaccompanied

withfats

torageintissues

othertha

nadiposetissue

(liverand

skeletal

muscle)whichmaylead

tolocalinsulinresistance

andstimulate

inflammation

Obesityc

hangesthe

morphologyand

compositionofadipose

tissue,leadingtochanges

initsproteinproduction

andsecre

tionincluding

pro-inflammatory

mediator

s


20/28

20 Arthritis

Table2:Continued.

Tajiketal.2

012inpress

Journalof

Endocrinological

Investigation[79]

Effectofd

iet-induced

weightlosson

inflammatorycytokines

inobesew

omen

Clinicaltrial

Subjects:Premenopa

usal

obesewomen(body

massindex

30)aged

21to54yearswithou

t

diabetes,hypertensio

n,

orhyperlipidemia

(n=

29)

Toevaluatechangesin

pro/anti-inflammatory

adipocytokinesand

metabolicprofileafter

moderatediet-induced

weight,anthropometric

parameters,lipidand

glucoseprofiles,IL-6,

IL-10,andIL-18were

measured

Subjectsthenenteredintoa

weightreductionprogram

(3months)

Bodymassindex,waist

circumference,triceps

skinfoldthickness,total

cholesterol,triglyceride,

andfastingplasma

glucosedecreased,w

hile

HDL-cholesterol

increased

Whileplasmalevelsof

IL-6andIL-18

decreased,nochange

wasobservedin

circulatinglevelsof

IL-10

Obesityisassociated

withlow-gradesystemic

inflammationwhichhas

beenlink

edtothe

increased

riskof

cardiovasculardisease

andtype

IIdiabetesin

obesepatients

improvedbody

compositioninducedby

restrictionofenergy

intakeisassociatedwith

favorable

serum

concentrationsofIL-6

andIL-18inobese

women

R

heumatoidarthritis

GremeseandFerraccioli

2011

Autoimmunology

Review[80]

Themetabolic

syndrome

:the

crossroadsbetween

rheumato

idarthritisand

cardiovascularrisk

Review

Rheumatoidarthritis(RA)

patientshaveanincidence

ofcardiovascular(CV)

diseasestwo-foldthatof

thegeneralpopulation

Atherosclerosis,themain

determinantofCV

morbidityandmortality,

andcarotidintima-media

thickness,anearly

preclinicalmarkerof

atherosclerosis,alsooccur

earlyoninRA


CVriskfactorsseemto

havethesame

prevalenceinRAand

non-RApatients,t

hus

theydonotfullyexplain

increasedCVburden,

suggestingthatRA

inflammationand

therapiesplayarolein

increasingCVriskin

thesepatients

Themetabolicsyndrome

(MetS)andfattissueare

likelymajorplayersin

thiscomplexnetwork

TheassociationofMetS

andatherosclerosisis

partlymediatedby

alteredsecretionof

adipokinesbyadipose

tissueand,

Obesityisnowregarded

asasystemic,low-grade

inflammatorystate,and

inflammationasalink

betweenobesity,

metabolicsyndrome,

andCVd

iseases

TocontrolCVrisk,data

supportthenecessityof

tightcontrolof

inflammationfromboth

RAandM

etS


21/28

Arthritis 21

Table2:Continued.

ontheotherhand,t

here

areevidencethat

adipokinesmayplaya

roleininflammatoryRA

Preteetal.,

2011

Autoimmunology

Review[81]

Extra-articular

manifestationsof

rheumato

idarthritis:An

update

Review

Rheumatoidarthritis

(RA)isan

immune-mediated

diseaseinvolvingchronic

low-gradeinflammation

thatmayprogressively

leadtojointdestruct

ion,

deformity,disability,

and

evendeath

Despiteitspredomin

ant

osteoarticularand

periarticular

manifestations,RAisa

systemicdiseaseoften

associatedwith

cutaneousand

organ-specific

extra-articular

manifestations(EAM

)

CurrentReviews

knowledgeaboutEAMin

termsoffrequency,c

linical

aspects,andcurrent

therapeuticapproaches.In

aninitialattemptata

classification,weseparated

EAMfromRA

co-morbiditiesandfrom

general,constitutional

manifestationsofsystemic

inflammation.E

AMwas

classifiedascutaneousand

visceralforms,bothsevere

andnotsevere


Inaggregateddatafrom

12largeRAcohorts,

patientswithEAM,

especiallythesevere

forms,werefoundto

havegreater

co-morbidityand

mortalitythanpatients

withoutEAM

Understa

ndingthe

complexityofEAMand

theirmanagement

remainsachallengefor

clinicians,especially

sincethe

effectivenessof

drugtherapyonEAM

awaitsstudy

Stroke

Denesetal.2

011

CerebrovascularDisease

[82]

Interleukin-1andstroke:

biomarker,harbingerof

damage,a

ndtherapeutic

target

Review

Inflammationisestablished

asacontributorto

cerebrovasculardisease

Riskfactorsforstroke

includemanyconditions

associatedwithchronicor

acuteinflammation,and

inflammatorychangesin

thebrainafter

cerebrovascularevents

contribute

Evidencesupports

importanceof

peripherally-derived

immunecellsand

inflammatorymolecules

invariouscentral

nervoussystem

disorders,including

stroke

Inflammatorycytokine,

interleukin-1(IL-1),

playsapivotalrolein

bothlocalandsystemic

Blockade

ofIL-1could

betherap

euticallyuseful

inseveraldiseaseswhich

areriskfactorsforstroke

Thereisconsiderable

preclinicalandclinical

evidence

thatinhibition

ofIL-1byIL-1receptor

antagonistmaybe

valuableinthe

managem

entofacute

stroke


22/28

22 Arthritis

Table2:Continued.

tooutcomeinexperimental

studies,withgrowing

evidencefromclinical

research


inflammationandisa

keydriverofperipheral

andcentralimmune

responsestoinfectionor

injury

Wuetal.,

2012

AmericanJournalof

RhinologicalAllergy

[83]

Riskofstrokeamong

patientsw

ith

rhinosinu

sitis:a

population-basedstudy

inTaiwan

Population-basedtrial

Prospectivecohortstudy

PatientsinTaiwan

(LongitudinalHealth

InsuranceDatabase2005

(LHID2005))whohad

receivedadiagnosisof

rhinosinusitis(n=

53,6

53)betweenJanuary

1,2004andDecember

31,2

005

Controlgroup(1:4)

drawnfromthesame

databasewasmatched

forageandgender(n

=

214,624)

Eachpatientwasfollowed

upusingdataentereduntil

theendof2006

Proportionalhazard

regressionswereperformed

toevaluatethehazard

ratios(HRs)afteradjusting

forpotentialconfounding

factors

Patientswith

rhinosinusitisweremore

likelytosufferstrokes

thanthecontrol

population,a

fter

adjustingforpotential

confounders

Bothacuteandchronic

sinusitisareriskfactors

ormarke

rsforstroke

thatisindependentof

traditionalstrokerisk

factors

Furthere

pidemiological

researchiswarranted


23/28

Arthritis 23

Table 3: Pro- and anti-inflammatory foods (Source: [8587]).

Proinflammatory foods Anti-inflammatory foods

AlcoholRegular high consumption irritates esophagus, larynx, andliver which can lead to chronic inflammation whichpromotes tumor growth at sites of chronic irritation

Cooking oilsA diet of high imbalance of omega-6 to omega-3 ratiopromotes inflammation (e.g., heart disease and cancer)Dairy productsMeat (commercially produced meats where animals are fedgrains such as soy beans and corns (a diet high ininflammatory omega-6 fatty acids and low inanti-inflammatory omega-3 fatty acids; also, these animalshave limited exercise and raised to gain excess fat, ending upwith high saturated fats. To make the animals grow faster andprevent them from getting sick, they are injected withhormones and fed antibiotics.)Red meats (beef, lambs and pork) and processed meats (has,sausages, and salami)

Red meat contains a molecule humans do not naturallyproduce (Neu5Gc) that leads to the production of antibodiesin defense of it, an immune response that may triggerchronic inflammation, and low grade inflammation (linkedto heart disease and cancer)Refined grains devoid of fiber and vitamin B compared withunrefined grains (have bran, germs and aleurone layer),refined grains like refined sugar with high glycemic indexWhen consistently consumed hasten onset heart disease andcancerAlso often laden with fat and sugar and artificial flavors andpartially hydrogenated oilArtificial food additivesAspartame and monosodium glutamate reportedly triggerinflammatory responses (particularly in those withinflammatory conditions, for example, rheumatoid arthritisSugarsTrans fats (found in deep fried foods, commercially bakedgoods, and those prepared with partially dehydrongenatedoil, margarine, and vegetable shortening

The anti-inflammatory nutritional plan includes thefollowing.

Avoidance of sweets and sugarAvoidance of high refined foods such as processedfoods (white bread and rice, and pasta)Minimal fats (virgin olive oil okay as it has excellentanti-inflammatory properties)High fiber foods including dark breads such as rye andpumpernickelNo alcoholRecommended anti-inflammatory foods:Oatmeal (not instant)Asparagus, avocado, beets, Brussel sprouts,broccoli, cauliflower, kale, parsnip, spinachRomaine lettuceBerriesStrawberries, blueberries, raspberries, blackberriesGreen apples, oranges, pears, lemons, cantaloupeMelonOlivesUnsalted raw nutsSunflower seedsExtra virgin olive oilWaterGreen teaBeans, chickpeas, black beansLentilsLow-fat turkey/chickenEggsSalmonLow-sodium tuna packed in water

DairyLow-fat milk products are acceptable particularly plain

yogurt, cottage, and solid cheeses, if any, like Swiss orcheddar, feta

physical activity. With respect to nutrition, basic assess-ment can be done and education undertaken regardingpatients knowledge with the inflammatory characteristics oftheir diets and incorporating anti-inflammatory foods (seeTable 3).

In addition, in the interest of best practice, as pri-mary nonpharmacologic practitioners, contemporary phys-ical therapists are integrating into practice health educa-tion including initiating and supporting smoking cessation,improved sleep hygiene, and stress management [94]. Giventhat smoking, poor sleep, and stress are all associated withlow-grade inflammation and hyperimmune response, teammembers such as nutritionists and health counselors couldbe used to greater advantage on the health care team topromote effective health education related to health behaviorchange. In acute conditions, such education needs to beintroduced potentially with pharmacologic intervention toreduce inflammation and pain expediently. However, as

the acute episode subsides and the condition stabilizes,medication needs to be reduced as much as possible, andperhaps completely, as health living practices take maximaleffect.

The benefits of healthy living have no better been

exemplified than in an elegant but simple study reported byFord and colleagues [95]. In their study of over 23,000 peoplebetween35 and 65 years old, they reported that over an eight-year period, people who did not smoke; had a body massindex of less than 30 kgm2; were physically active for at least3.5 hours weekly; and ate healthily reduced their risk of type2 diabetes mellitus by 93%, myocardial infarction by 81%,stroke by 50%, and cancer by 36%. Even if not all four healthbehaviors were present, risk of developing a chronic lifestyle-related condition decreased commensurate with an increasein the number of positive lifestyle factors. Furthermore,health-related quality of life increased with the number ofhealthy lifestyle behaviors that participants reported. In the


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process of conducting the present review of the literature,we identified no medication that was associated with suchoutcomes and such low risk of side effects, if any.

In the interest of best practice, healthy living recom-mendations need to be prescribed as uniquely for theirdirect effects on the pathoetiology of osteoarthritis, and

prescribed as aggressively as first-line medications. Althoughgeneral health recommendations are important for healthpromotion and disease prevention generally, the tenets ofhealthy living need to be systematically targeted to thepatients signs and symptoms and prescribed accordinglyincluding long-term followup and support. Not doing sodeprives the patient of evidence-informed best practiceosteoarthritis management and care.

Consistent with healthy living as a first-line approach,patients health behaviors need to be assessed in a measur-able, reproducible, and standardized manner. In additionto questionnaires and self-reports, despite their limitations,inflammatory biomarkers such as C-reactive protein may beuseful to objectively measure the effects of lifestyle behaviorchange rather than simply as an index of cardiovascular anddiabetes risk [9699].

To address the reports of health care practitioners aboutlack of knowledge and confidence to effect health behaviorchange, they have a range of evidence-based interventionsat their disposal that are not time or resource intense [100102]. In addition, the 5s approach of behavior change, forexample, has some evidence base and has been endorsed bythe World Health Organization [103]. Its simplicity makesit attractive to health professionals, that is, assess: evaluatebehavior change status (and progress), advise: personallyrelevant behavioral recommendations, agree: set specific col-laborative, feasible goals, assist: anticipate barriers, problem-solve solutions, and complete action plan, and arrange:schedule followup, contacts, and resources.

In the interest of best practice, lifestyle behaviors needto be systematically assessed in every patient and moni-tored across the health professions the patient is seeing.Healthy living recommendations need to be prescribed asuniquely for their direct effects on the pathoetiology ofosteoarthritis as medications are, and as aggressively if first-line management is to truly reflect evidence-based practice.Although general recommendations are important for healthpromotion and disease prevention generally, healthy livingrecommendations must be systematically targeted to thepatients signs and symptoms. In addition to integrating

dietary and activity recommendations, smoking cessation,sleep hygiene, and stress reduction should be included inthe interest of comprehensive effective care. Not doing sodeprives the patient of best practice osteoarthritis manage-ment in relation to potential comorbidities that commonlypresent in this cohort.

5. Implications: Clinical and Research

The evidence supporting lifestyle behaviour change toaddress low-grade inflammation in people with oste-oarthritis often with coexistent lifestyle-related risk factors

and low-grade inflammatory conditions (specifically, anti-inflammatory nutritional regimens, and moderate physicalactivity) is unequivocal. The evidence is sufficiently com-pelling for related healthy living assessment and recommen-dations be a component of first-line best practice in themanagement of the signs and symptoms of people with

osteoarthritis. Assessments need to include lifestyle profilesrelated to body mass index, waist girth, and waist-to-hipratio; physical activity and exercise, as well as smoking, sleeppatterns, and stress (as these three latter factors have alsobeen reported to be proinflammatory). When quantifiedin standardized ways, these profiles can serve as clinicaloutcomes to assess health behavior change interventions. Thehealth behaviour change literature has exploded over the pasttwo decades, yet health professions report lack of confidencein effecting health behavior change in their patients, andlack of resources including time [100]. Although muchneeds to be done, evidence-based interventions can bereadily integrated into the framework of clinical practice andpatient visits [101, 104], for example, brief advice, referralto others professionals, and followup). Physical therapistsare particularly well positioned for initiating and supportinghealth behavior change in that patient visits tend to beprolonged and protracted over time, elements that are criticalto effective long-term sustained health behavior change.

Studies are needed to examine the differentiating char-acteristics of those people with osteoarthritis who respondprimarily to optimal nutrition and moderate physical activ-ity, and those who do not. In addition, the elements of ananti-inflammatory nutrition regimen and moderate physicalactivity program need to be refined in terms of theirprescriptive parameters, specifically, which elements shouldbe a primary focus for which patients. Another line of studiesis needed to examine the effect of such healthy lifestylechoices that increase inflammation threshold, on the needfor medication and, if medication is indicated, how mightits potency and dosage be reduced. The interactions amonghealthy lifestyle behaviors and pharmacokinetics need to beelucidated. Given that chronic systemic low-grade inflam-mation has been reported to be a common denominator oflifestyle-related conditions, studies are needed to establishthe degree to which their risk factors and manifestations arereduced in people with chronic osteoarthritis whose first-line management includes prescribing optimal nutrition andphysical activity for their anti-inflammatory effects. Further-more, the impact of low-grade inflammation can be more far

reaching than physical complaints alone, in that even healthyolder adults report poorer health commensurate with levelof inflammatory markers [105]. Lastly, all indicators supportthat the approach to chronic progressive conditions suchas osteoarthritis needs to be holistic and interprofessional[106]. Research is needed to capture the breadth of thisevidence-informed practice approach.

6. Conclusion

Based on the extant literature, exploitation of anti-in-flammatory lifestyle behavior change as first-line interven-tion in the management of chronic osteoarthritis could well


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constitute best practice. Chronic low-grade inflammationthat has been reported in chronic osteoarthritis is compa-rable to other lifestyle-related conditions supporting a com-mon mechanism of action. Addressing chronic low-gradeinflammation by focussing on lifestyle factors that contributedirectly to it holds the promise of increasing a patients

inflammatory threshold, reducing rate of disease progres-sion, reducing weight, and maximizing health by minimizinga patients risk or manifestations of other lifestyle-relatedconditions. Even in part, such outcomes could minimizedemands on physicians for short-term symptom reduction,and management of the patients comorbidity related tolifestyle-related conditions. First-line lifestyle interven-tions to address chronic low-grade inflammation provides aninformed cost-effective basis for the 21st century prevention,potential reversal, and management of chronic osteoarthritis.Exploitation of such first-line intervention, however, needsto be a goal shared and supported by all healthcare teammembers.

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