chronic low-grade inflammation associated with osteoarthritis
TRANSCRIPT
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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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Arthritis 9
Table2:Continued.
Cancer
CorreaandPiazuelo,
2012[53]
Thegastricprecancerous
cascade
Leadarticle
State-of-the-art
Reviewofexperimental
articlesthatsupportthe
stepsinthegastric
precancerouscascade
Searchstrategyunspecified
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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10 Arthritis
Table2:Continued.
variables,
bycreatinganew,locally
stable,a
lternative
equilibriumforthe
dynamicsystem,in
additiontoitsnormal
(homeostatic)equilibrium
Searchstrategyunspecified
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
Searchstrategyunspecified
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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Arthritis 11
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)
Searchstrategyunspecified
Spilloverof
inflammatorymediators
intothecirculation
consideredthesourceof
systemicinflammation
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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12 Arthritis
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,
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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,
highsensitiveC-reactive
protein,andleptin
Bloodpressure,leptin,h
igh
sensitiveC-reactiveprotein,
andHOMA-IRwere
determinedatbaselineand
after3monthsofquinapril
treatment
Aftertreatmentwith
quinaprilHOMA-IR,
highsensitiveC-reactive
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
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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
Searchstrategyunspecified
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)
Searchstrategyunspecified
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
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Arthritis 15
Table2:Continued.
Ischemicheartdisease
Simon,2
012
CirculationJournal[69]
Inflamma
tionand
vascularinjury
Review
Toexaminethe
centralroleof
inflammationinvascular
injuryandrepair
Searchstrategyunspecified
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
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16 Arthritis
Table2:Continued.
Someinfectionscouldhave
aroleonthegenesisand
developmentofdamageto
thevascularwallandof
atheromatousplaqueHP
couldinfluencethe
developmentofIHD
throughvariouspathways
Searchstrategyunspecified
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
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Arthritis 17
Table2:Continued.
Luis-Rodrguezetal.,
2012
WorldJournalof
Diabetes[74]
Pathophysiologicalrole
andtherapeutic
implicatio
nsof
inflammationindiabetic
nephropathy
Review(experimental
andclinicalstudies)
Toidentifypathogenic
pathwaysforearlier
diagnosisandtargeting
noveltreatments
Searchstrategyunspecified
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
Searchstrategyunspecified
Obesity-related
glomerulopathyisa
majorcauseofend-stage
renaldisease.
Obesityhasbeen
consideredastateof
chroniclow-grade
systemicinflammation
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
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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
systemicinflammation,
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
Searchstrategyunspecified
Pathobiologyofobesity
andosteoarthritis(OA)
wasexamined,aswellas
literaturetheunderlying
systemicinflammation,
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
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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
Searchstrategyunspecified
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
Searchstrategyunspecified
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
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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
Searchstrategyunspecified
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
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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
Searchstrategyunspecified
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
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22 Arthritis
Table2:Continued.
tooutcomeinexperimental
studies,withgrowing
evidencefromclinical
research
Searchstrategyunspecified
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
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fter
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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.
References
[1] L. Brosseau, G. A. Wells, P. Tugwell et al., Ottawapanelevidence-based clinical practice guidelines for the manage-ment of osteoarthritis in adults who areobese or overweight,Physical Therapy, vol. 91, no. 6, pp. 843860, 2011.
[2] M. C. Hochberg, R. D. Altman, K. T. April et al., AmericanCollege of Rheumatology 2012. Recommendations for theuse of nonpharmacologic and pharmacologic therapies inosteoarthritis of the hand, hip, and knee, Arthritis CareResearch, vol. 64, pp. 465474, 2012.
[3] N. E. Lane and J. M. Thompson, Management ofosteoarthritis in the primary-care setting: an evidence- based
approach to treatment, American Journal of Medicine A, vol.103, no. 6, pp. 25S30S, 1997.[4] Osteoarthritis, National clinical guideline for care and
management in adults, The National Collaborative Cen-tre for Chronic Conditions. Royal College of Physi-cians of London, http://bookshop.rcplondon.ac.uk/contents/pub242-66a1af7e-27ae-4121-bd84-6b503c80a64e.pdf, 2008.
[5] W. Zhang, G. Nuki, R. W. Moskowitz et al., OARSI recom-mendations forthe management of hip and knee osteoarthri-tis. Part III: changes in evidence following systematic cumu-lative update of research published through January 2009,Osteoarthritis and Cartilage, vol. 18, no. 4, pp. 476499, 2010.
[6] A. Barr and P. G. Conaghan, Osteoarthritis: a holisticapproach, Clinical Medicine, vol. 12, no. 2, pp. 153155,2012.
[7] N. Hairon, New guidance on osteoarthritis focuses onpatient education, Nursing times, vol. 104, no. 10, pp. 2122,2008.
[8] R. I. Issa and T. M. Griffin, Pathobiology of obesity andosteoarthritis: integrating biomechanics and inflammation,Pathobiology of Aging and Age Related Diseases, vol. 2012,Article ID 17470, 2 pages, 2012.
[9] D. L. Cecil, K. Johnson, J. Rediske, M. Lotz, A. M. Schmidt,and R. Terkeltaub, Inflammation-induced chondrocytehypertrophy is driven by receptor for advanced glycation endproducts, Journal of Immunology, vol. 175, no. 12, pp. 82968302, 2005.
[10] J. Rojas-Rodrguez, L. E. Escobar-Linares, M. Garcia-Carrasco, R. O. Escarcega, S. Fuentes-Alexandro, and A.
Zamora-Ustaran, The relationship between the metabolicsyndrome and energy-utilization deficit in the pathogenesisof obesity-induced osteoarthritis, Medical Hypotheses, vol.69, no. 4, pp. 860868, 2007.
[11] N. Schlesinger and R. G. Thiele, The pathogenesis of boneerosions in gouty arthritis, Annals of the Rheumatic Diseases,vol. 69, no. 11, pp. 19071912, 2010.
[12] M. D. Smith, S. Triantafillou, A. Parker, P. P. Youssef, and M.Coleman, Synovial membrane inflammation and cytokineproduction in patients with early osteoarthritis, Journal ofRheumatology, vol. 24, no. 2, pp. 365371, 1997.
[13] E. Dean, S. Al-Obaidi, A. D. de Andrade et al., The firstphysical therapy summit on global health: implications andrecommendations for the 21st century, Physiotherapy Theoryand Practice, vol. 27, no. 8, pp. 531547, 2011.
[14] World Health Organization, Chronic Diseases, http://www.who.int/topics/chronic diseases/en/, 2005.
[15] P. Carrera-Bastos, M. Fontes-Villalba, J. H. O. Keefe, S.Lindeberg, and L. Cordain, The western diet and lifestyleand diseases of civilization, Research Reports in ClinicalCardiology, vol. 2, pp. 1535, 2012.
[16] B. Caballero, Obesity as a consequence of undernutrition,Journal of Pediatrics, vol. 149, no. 3, pp. S97S99, 2006.
[17] G. Engstrom, M. Gerhardsson de Verdier, J. Rollof, P. M.Nilsson, and L. S. Lohmander, C-reactive protein, metabolicsyndrome and incidence of severe hip and knee osteoarthri-tis. A population-based cohort study, Osteoarthritis andCartilage, vol. 17, no. 2, pp. 168173, 2009.
[18] L. Landaeta-Daz, J. M. Fernandez, M. Da Silva-Grigoletto etal., Mediterranean diet, moderate-to-high intensitytrainingand health-related quality of life in adults with metabolicsyndrome, European Journal of Preventive Cardiology. Inpress.
[19] T. C. Campbell, A study on diet, nutrition and disease in thePeoples Republic of China. Part I, Boletin de la Asociacion
Medica de Puerto Rico, vol. 82, no. 3, pp. 132134, 1990.[20] T. C. Campbell and C. Junshi, Diet and chronic degenerative
diseases: perspectives from China, American Journal ofClinical Nutrition, vol. 59, supplement 1, pp. 1153S1153S,1994.
[21] T. C. Campbell and T. M. Campbell, The China Study,Benbella Books, Dallas, Tex, USA, 2006.
[22] T. C. Campbell, B. Parpia, and J. Chen, Diet, lifestyle, andthe etiology of coronary artery disease: the Cornell ChinaStudy, American Journal of Cardiology B, vol. 82, no. 10, pp.18T21T, 1998.
[23] S. Gregersen, D. Samocha-Bonet, L. K. Heilbronn, and L. V.Campbell, Inflammatory and oxidative stress responses tohigh-carbohydrate and high-fat meals in healthy humans,
Journal of Nutrition and Metabolism, vol. 2012, Article ID
238056, 8 pages, 2012.[24] B. J. Nicklas, W. Ambrosius, S. P. Messier et al., Diet-
induced weight loss, exercise, and chronic inflammation inolder, obese adults: a randomized controlled clinical trial,
American Journal of Clinical Nutrition, vol. 79, no. 4, pp. 544551, 2004.
[25] M. A. Allison, N. E. Jensky, S. J. Marshall, A. G. Bertoni, andM. Cushman, Sedentary behavior and adiposity-associatedinflammation: the multi-ethnic study of atherosclerosis,
American Journal of Preventive Medicine, vol. 42, no. 1, pp.813, 2012.
[26] M. Gleeson, N. C. Bishop, D. J. Stensel, M. R. Lindley, S. S.Mastana, and M. A. Nimmo, The anti-inflammatory effectsof exercise: mechanisms and implications for the prevention
-
7/30/2019 Chronic Low-Grade Inflammation Associated With Osteoarthritis
26/28
26 Arthritis
and treatment of disease, Nature Reviews Immunology, vol.11, no. 9, pp. 607615, 2011.
[27] A. M. W. Petersen and B. K. Pedersen, The anti-inflam-matory effect of exercise, Journal of Applied Physiology, vol.98, no. 4, pp. 11541162, 2005.
[28] Exercise helps ease arthritis pain and stiffness, http://www.mayoclinic.com/health/arthritis/AR00009, 2012.
[29] N. P. Walsh, M. Gleeson, R. J. Shephard et al., Positionstatement. Part one: immune function and exercise, ExerciseImmunology Review, vol. 17, pp. 663, 2011.
[30] M. Gurevich, P. M. Kohn, and C. Davis, Exercise-inducedanalgesia and the role of reactivity in pain sensitivity, Journalof Sports Sciences, vol. 12, no. 6, pp. 549559, 1994.
[31] R. B. Singh, G. Dubnov, M. A. Niaz et al., Effect of an Indo-Mediterranean diet on progression of coronary artery diseasein high risk patients (Indo-Mediterranean Diet Heart Study):a randomised single-blind trial, The Lancet, vol. 360, no.9344, pp. 14551461, 2002.
[32] J. Lee, V. Taneja, and R. Vassallo, Cigarette smoking andinflammation cellular and molecular mechanisms, Journalof Dental Research, vol. 91, no. 2, pp. 142149, 2012.
[33] R. B. Goncalves, R. D. Coletta, K. G. Silverio et al.,Impact of smoking on inflammation: overview of molecularmechanisms, Inflammation Research, vol. 60, no. 5, pp. 409424, 2011.
[34] A. Bakhru and T. P. Erlinger, Smoking cessation andcardiovascular disease risk factors: results from the thirdnational health and nutrition examination survey, PLoS
Medicine, vol. 2, no. 6, pp. 05280536, 2005.[35] Z. Baka, E. Buzas, and G. Nagy, Rheumatoid arthritis and
smoking: putting the pieces together, Arthritis Research &Therapy, vol. 11, no. 4, p. 238, 2009.
[36] S. Amin, J. Niu, A. Guermazi et al., Cigarette smoking andthe risk for cartilage loss and knee pain in men with kneeosteoarthritis, Annals of the Rheumatic Diseases, vol. 66, no.1, pp. 1822, 2007.
[37] P. H. Black, Stress and the inflammatory response: a reviewof neurogenic inflammation, Brain, Behavior, and Immunity,vol. 16, no. 6, pp. 622653, 2002.
[38] P. H. Black, The inflammatory response is an integral part ofthe stress response: implications for atherosclerosis, insulinresistance, type II diabetes and metabolic syndrome X,Brain, Behavior, and Immunity, vol. 17, no. 5, pp. 350364,2003.
[39] S. Cohen, D. Janicki-Deverts, W. J. Doyle et al., Chronicstress, glucocorticoid receptor resistance, inflammation, anddisease risk, Proceedings of the National Academy of Science,vol. 109, no. 16, pp. 59955999, 2012.
[40] M. Maes, Psychological stress and the inflammatoryresponse system, Clinical Science, vol. 101, no. 2, pp. 193
194, 2001.[41] T. Pedersen, Lack of sleep, stress leads to inflammation in
older adults, Psychology Central, http://psychcentral.com/news/2012/03/02/lack-of-sleep-stress-leads-to-inflammati-on-in-older-adults/35490.html, 2012.
[42] B. Giunta, F. Fernandez, W. V. Nikolic et al., Inflammagingas a prodrome to Alzheimers disease, Journal of Neuroin-
flammation, vol. 5, p. 51, 2008.[43] R. Veerhuis, Histological and direct evidence for the role
of complement in the neuroinflammation of AD, CurrentAlzheimer Research, vol. 8, no. 1, pp. 3458, 2011.
[44] G. Candore, C. Caruso, E. Jirillo, T. Magrone, and S.Vasto, Low grade inflammation as a common pathogeneticdenominator in age-related diseases: novel drug targets for
anti-ageing strategies and successful ageing achievement,Current Pharmaceutical Design, vol. 16, no. 6, pp. 584596,2010.
[45] K. T. Chou, C. C. Huang, Y. M. Chen et al., Asthma andrisk of erectile dysfunction-A nationwide population-basedstudy, Journal of Sexual Medicine, vol. 8, no. 6, pp. 17541760, 2011.
[46] A. Dixon, The treatment of asthma in obesity, ExpertReviews in Respiratory Medicine, vol. 6, no. 3, pp. 331340,2012.
[47] C. T. Juel, Z. Ali, L. Nilas, and C. S. Ulrik, Asthmaand obesity: does weight loss improve asthma control? Asystematic review, Journal of Asthma and Allergy, vol. 5, pp.2126, 2012.
[48] H. F. Gu, C. K. Tang, and Y. Z. Yang, Psychological stress,immune response, and atherosclerosis, Atherosclerosis, vol.223, no. 1, pp. 6977, 2012.
[49] E. J. Kucharz, Chronic inflammation-enhanced atheroscle-rosis: can we consider it as a new clinical syndrome? MedicalHypotheses, vol. 78, no. 3, pp. 396397, 2012.
[50] X. T. Lu, Y. F. Liu, L. Zhang et al., Unpredictable chronic
mild stress promotes atherosclerosis in high cholesterol-fedrabbits, Psychosomatic Medicine, vol. 74, no. 6, pp. 604611,2012.
[51] E. Ortega, R. Gilabert, I. Nunez et al., White blood cellcount is associated with carotid and femoral atherosclerosis,
Atherosclerosis, vol. 221, no. 1, pp. 275281, 2012.
[52] A. Pinto, D. Di Raimondo, A. Tuttolomondo, C. Butta, G.Milio, and G. Licata, Effects of physical exercise on inflam-matory markers of atherosclerosis, Current PharmaceuticalDesign, vol. 18, no. 28, pp. 43264349, 2012.
[53] P. Correa and M. B. Piazuelo, The gastric precancerouscascade, Journal of Digestive Diseases, vol. 13, no. 1, pp. 29, 2012.
[54] S. Peters, N. Grunwald, P. Rummele et al., Chronic psy-
chosocial stress increases the risk for inflammation-relatedcolon carcinogenesis in male mice, Stress, vol. 15, no. 4, pp.403415, 2012.
[55] L. A. Cox Jr, Dose-response thresholds for progressivediseases, Dose Response, vol. 10, no. 2, pp. 233250, 2012.
[56] A. Lindberg, L. G. Larsson, E. Ronmark, and B. Lundback,Co-morbidity in mild-to-moderate COPD: comparison tonormal and restrictive lung function, Chronic ObstructivePulmonary Disease, vol. 8, no. 6, pp. 421428, 2011.
[57] N. H. T. ten Hacken, Physical inactivity and obesity: relationto asthma and chronic obstructive pulmonary disease?Proceedings of the American Thoracic Society, vol. 6, no. 8, pp.663667, 2009.
[58] E. F. M. Wouters, N. L. Reynaert, M. A. Dentener, and J.
H. J. Vernooy, Systemic and local inflammation in asthmaand chronic obstructive pulmonary disease is there a connec-tion? Proceedings of the American Thoracic Society, vol. 6, no.8, pp. 638647, 2009.
[59] C. M. Chang, C. J. Hsieh, J. C. Huang, and I. C. Huang,Acute and chronic fluctuations in blood glucose levels canincrease oxidative stress in type 2 diabetes mellitus, ActaDiabetologica, vol. 49, no. 1 Supplement, pp. 171177, 2012.
[60] B. C. van Bussel, S. S. Soedamah-Muthu, R. M. Henry etal., EURODIAB Prospective Complications Study Group,Unhealthy dietary patterns associated with inflammation andendothelial dysfunction in type 1 diabetes: The EURODIABstudy, Nutrition and Metabolism in Cardiovascular Disease.In press.
-
7/30/2019 Chronic Low-Grade Inflammation Associated With Osteoarthritis
27/28
Arthritis 27
[61] D. Kadetoff, J. Lampa, M. Westman, M. Andersson, and E.Kosek, Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels, Journal of
Neuroimmunology, vol. 242, no. 1-2, pp. 3338, 2012.
[62] E. Ortega, M. E. Bote, E. Giraldo, and J. J. Garc a, Aquaticexercise improves the monocyte pro- and anti-inflammatorycytokine production balance in fibromyalgia patients, Scan-
dinavian Journal of Medical Science and Sports, vol. 22, no. 1,pp. 104112, 2012.
[63] A. Berni, E. Ciani, M. Bernetti et al., Renal resistiveindex and low-grade inflammation in patients with essentialhypertension, Journal of Human Hypertension, vol. 26, no.12, p