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Hindawi Publishing CorporationArthritisVolume 2012, Article ID 560634, 28 pagesdoi:10.1155/2012/560634
Review Article
Prescribing Optimal Nutrition and Physical Activity as“First-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, elizabeth.dean@ubc.ca
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 ideain 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 patient’s 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 physicalactivity, and on pharmacological support for inflammationand pain [1–5]. 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
2 Arthritis
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 people’s 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 [19–22] 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, exercise’s anti-inflammatory effects are notdiscussed in established practice guidelines [1–5]. In sum, thewestern lifestyle is inherently unhealthy, and lifestyles withnonwestern 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[37–40] 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 completelyunderstood, 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
Arthritis 3
Physical inactivity
Altered biomechanicsJoint stiffnessJoint pain
Physical limitations
Energetic imbalance
Proinflammatory
effects of diet
Adipose tissue
inflammatory effectsChronic low-grade
systemic
inflammation
OverweightObesity 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 inadministration 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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dysf
un
ctio
n(E
D)
Subj
ects
wit
has
thm
aex
per
ien
ced
1.9-
fold
incr
ease
inE
Din
depe
nde
nt
ofag
ean
dco
mor
bidi
tyco
mpa
red
wit
hco
ntr
olco
hor
t
Ast
hm
am
aybe
anin
depe
nde
nt
risk
fact
orfo
rE
D(i
ncr
easi
ng
wit
has
thm
ase
veri
ty)
Ch
ron
icsy
stem
icin
flam
mat
ion
isim
plic
ated
inth
islin
kage
Dix
on,2
012
Exp
ert
Rev
iew
sin
Res
pira
tory
Med
icin
e[4
6]
Th
etr
eatm
ent
ofas
thm
ain
obes
ity
Exp
ert
revi
ew
Epi
dem
iolo
gyof
obes
ity
has
infl
uen
ced
epid
emio
logy
ofot
her
con
diti
ons,
for
exam
ple,
asth
ma
Obe
sity
maj
orri
skfa
ctor
for
new
asth
ma
Sear
chst
rate
gyn
otsp
ecifi
ed
Mec
han
ical
fact
ors,
met
abol
icin
flam
mat
ion
,an
dot
her
com
orbi
diti
espr
obab
lyco
ntr
ibu
teto
asth
ma
Th
erap
ies
nee
dto
bede
velo
ped
and
tailo
red
tova
riou
su
nde
rlyi
ng
mec
han
ism
s
Juel
etal
.,20
12Jo
urn
alof
Ast
hm
aan
dA
llerg
y[4
7]
Ast
hm
aan
dob
esit
y:do
esw
eigh
tlo
ssim
prov
eas
thm
aco
ntr
ol?
Asy
stem
atic
revi
ew
Syst
emat
icre
view
Obe
sity
asso
ciat
edw
ith
hig
has
thm
ain
cide
nce
and
poor
con
trol
Rev
iew
ofkn
owle
dge
oneff
ect
ofw
eigh
tre
duct
ion
onas
thm
aco
ntr
olba
sed
onsy
stem
atic
sear
ches
usi
ng
the
Pu
bMed
data
base
and
rele
van
tM
eSH
term
s
Wei
ght
loss
inob
ese
indi
vidu
als
asso
ciat
edw
ith
48%
–100
%re
mis
sion
ofas
thm
asy
mpt
oms
Wei
ght
loss
asso
ciat
edw
ith
impr
oved
lun
gfu
nct
ion
and
airw
ayre
spon
sive
nes
sto
inh
aled
met
hac
hol
ine
Wei
ght
loss
con
sist
entl
yre
duce
sas
thm
asy
mpt
oms
Impr
oved
asth
ma
con
trol
incl
udi
ng
obje
ctiv
em
easu
res
ofdi
seas
eac
tivi
ty
Ath
eros
cler
osis
Gu
etal
.,20
12A
ther
oscl
eros
is[4
8]
Psyc
hol
ogic
alst
ress
,im
mu
ne
resp
onse
,an
dat
her
oscl
eros
isR
evie
w
Syn
thes
isof
evid
ence
sth
atva
riou
sim
mu
nol
ogic
alfa
ctor
sar
etr
ansf
orm
edu
nde
rpr
olon
ged
psyc
hol
ogic
alst
ress
byca
usi
ng
vasc
ula
rlo
w-g
rade
infl
amm
atio
n
Evid
ence
supp
orts
expr
essi
onof
pro-
and
anti
-in
flam
mat
ory
cyto
kin
esby
stre
ssh
orm
ones
(cat
ech
olam
ines
and
cort
icos
tero
ids)
Elu
cida
tion
oftw
o-w
ayco
mm
un
icat
ion
betw
een
neu
roen
docr
ine
and
imm
un
esy
stem
sIm
plic
atio
ns
for
targ
eted
trea
tmen
tst
rate
gies
8 Arthritis
Ta
ble
2:C
onti
nu
ed.
Ku
char
z,20
12M
edic
alH
ypot
hes
es[4
9]
Ch
ron
icin
flam
mat
ion
-en
han
ced
ath
eros
cler
osis
:can
we
con
side
rit
an
ewcl
inic
alsy
ndr
ome?
Nar
rati
vere
view
Med
ical
hypo
thes
is:
inci
den
ceof
card
iova
scu
lar
dise
ase
(CV
D)
inpa
tien
tsw
ith
chro
nic
auto
imm
un
edi
sord
ers
ism
uch
hig
her
than
inge
ner
alpo
pula
tion
CV
Dis
cau
sed
byac
cele
rate
dat
her
oscl
eros
is,i
nw
hic
hch
ron
icin
flam
mat
ion
isim
plic
ated
Th
elit
erat
ure
sear
chst
rate
gies
un
spec
ified
Ch
ron
icin
flam
mat
ion
-en
han
ced
ath
eros
cler
osis
syn
drom
eis
prop
osed
asa
sepa
rate
syn
drom
eoc
curr
ing
inpa
tien
tssu
ffer
ing
ofch
ron
icin
flam
mat
ion
Ath
eros
cler
osis
asan
infl
amm
ator
ydi
seas
ean
dch
ron
icex
trav
ascu
lar
infl
amm
atio
nh
ave
com
mon
mec
han
ism
sre
sult
ing
inan
incr
ease
inat
her
oscl
eros
isan
dit
sse
quel
ae,C
VD
Luet
al.,
2012
Psyc
hos
omat
icM
edic
ine
[50]
Un
pred
icta
ble
chro
nic
mild
stre
sspr
omot
esat
her
oscl
eros
isin
hig
hch
oles
tero
l-fe
dra
bbit
s
Exp
erim
enta
l
Ch
ron
icps
ych
olog
ical
stre
ssas
soci
ated
incr
ease
dw
ith
risk
ofat
her
oscl
eros
isSt
udy
ofeff
ects
ofch
ron
icst
ress
onat
her
ogen
esis
inra
bbit
sR
abbi
tsfe
dch
oles
tero
l-ri
chdi
etfo
r4–
16w
ks
Hig
h-c
hol
este
rolf
eedi
ng
resu
lted
inhy
per
chol
este
role
mia
and
form
atio
nof
ath
eros
cler
otic
plaq
ues
inth
eao
rta
Hig
h-c
hol
este
rold
iet
incr
ease
dpl
aqu
esi
zean
din
stab
ility
Fin
din
gssu
ppor
tth
atat
her
oscl
eros
isis
augm
ente
dby
chro
nic
psyc
hol
ogic
alst
ress
,du
eto
incr
ease
dva
scu
lar
infl
amm
atio
nan
dde
crea
sed
endo
thel
ial
nit
ric
oxid
ebi
oava
ilabi
lity
Ort
ega
etal
.,20
12A
ther
oscl
eros
is[5
1]
Wh
ite
bloo
dce
llco
un
tis
asso
ciat
edw
ith
caro
tid
and
fem
oral
ath
eros
cler
osis
Clin
ical
stu
dySu
bjec
tsw
ith
dysl
ipid
emia
(n=
554)
and
sex-
mat
ched
nor
mol
ipid
emic
subj
ects
(n=
246)
Exa
min
edth
eas
soci
atio
nbe
twee
nin
flam
mat
ory
mar
kers
and
ath
eros
cler
osis
evid
ence
Car
otid
and
fem
oral
arte
ries
wer
eim
aged
Wh
ite
bloo
dce
llco
un
ts(W
BC
C)
wer
eob
tain
ed
Ch
ron
iclo
w-g
rade
infl
amm
atio
nis
asso
ciat
edw
ith
ath
eros
cler
osis
WB
CC
asso
ciat
edw
ith
mea
sure
sof
ath
eros
cler
osis
inde
pen
den
tof
risk
fact
ors
WB
CC
isa
use
fula
nd
easy
mar
ker
ofat
her
oscl
eros
is,
con
sist
ent
wit
hit
sin
flam
mat
ory
basi
s
Pin
toet
al.,
2012
Cu
rren
tP
har
mac
euti
cal
Des
ign
[52]
Eff
ects
ofph
ysic
alex
erci
seon
infl
amm
ator
ym
arke
rsof
ath
eros
cler
osis
Exp
ert
nar
rati
vere
view
Syn
thes
isof
rese
arch
rela
ted
tore
gula
rph
ysic
altr
ain
ing
and
low
-gra
dein
flam
mat
ion
Sear
chst
rate
gyu
nsp
ecifi
ed
Phy
sica
lexe
rcis
eco
uld
beco
nsi
dere
da
use
ful
wea
pon
agai
nst
loca
lva
scu
lar
and
syst
emic
infl
amm
atio
nin
ath
eros
cler
osis
.
Seve
ralm
ech
anis
ms
expl
ain
the
posi
tive
effec
tof
chro
nic
exer
cise
Incl
udi
ng
decr
ease
din
flam
mat
ion
and
endo
thel
iald
ysfu
nct
ion
,an
dm
odu
late
dpr
ogre
ssio
nof
un
derl
yin
gdi
seas
epr
ogre
ss
Arthritis 9
Ta
ble
2:C
onti
nu
ed.
Can
cer
Cor
rea
and
Pia
zuel
o,20
12[5
3]T
he
gast
ric
prec
ance
rou
sca
scad
eLe
adar
ticl
eSt
ate-
of-t
he-
art
Rev
iew
ofex
per
imen
tal
arti
cles
that
supp
ort
the
step
sin
the
gast
ric
prec
ance
rou
sca
scad
eSe
arch
stra
tegy
un
spec
ified
Infl
amm
ator
ych
ange
sm
ayp
ersi
stth
rou
ghou
tth
epr
ecan
cero
us
proc
ess
Firs
tre
cogn
ized
his
tolo
gica
lch
ange
isac
tive
chro
nic
infl
amm
atio
nw
hic
his
the
firs
tst
epin
the
prec
ance
rou
sca
scad
e
Mos
tpr
omis
ing
stra
tegy
for
con
trol
ofth
eco
ndi
tion
ispr
even
tion
,au
gmen
ted
bypr
olon
gin
gth
epr
e-ca
nce
rou
spr
oces
sw
hic
hre
quir
esan
un
ders
tan
din
gof
the
prec
ance
rou
sca
scad
eLe
sion
dete
cted
earl
iest
inin
flam
mat
ion
Pete
rset
al.2
012
Stre
ss[5
4]
Ch
ron
icps
ych
osoc
ial
stre
ssin
crea
ses
the
risk
for
infl
amm
atio
n-r
elat
edco
lon
carc
inog
enes
isin
mal
em
ice
Exp
erim
enta
lA
nim
alm
odel
Inve
stig
ated
the
effec
tsof
chro
nic
psyc
hos
ocia
lst
ress
inm
ale
mic
ew
ith
arti
fici
ally
indu
ced
colo
rect
alca
nce
r(C
RC
)
Ou
tcom
esba
sed
onco
lon
osco
pic
eval
uat
ion
and
prot
ein
anal
ysis
CSC
mic
esh
owed
acce
lera
ted
mac
rosc
opic
lesi
ons
CSC
mic
esh
owed
mor
ece
lldy
spla
sia
than
the
sin
gle-
hou
sed
con
trol
(SH
C)
mic
eA
bnor
mal
prot
ein
expr
essi
onw
asal
sogr
eate
rin
CSC
than
SHC
mic
e
Fin
din
gsco
nsi
sten
tw
ith
the
fact
that
chro
nic
psyc
hos
ocia
lstr
ess
incr
ease
sth
elik
elih
ood
ofde
velo
pin
gan
irri
tabl
ebo
wel
,an
dm
ult
iple
typ
esof
mal
ign
ant
neo
plas
ms,
incl
udi
ng
CR
C
Ch
ron
icob
stru
ctiv
elu
ng
dise
ase
Cox
jr20
12D
ose
Res
pon
se[5
5]
Dos
e-re
spon
seth
resh
olds
for
prog
ress
ive
dise
ases
Nar
rati
vere
view
Topr
ovid
eev
iden
ceba
sefo
rfr
amew
ork
Fram
ewor
kpr
opos
edfo
ru
nde
rsta
ndi
ng
how
expo
sure
can
dest
abili
zen
orm
ally
hom
eost
atic
feed
back
con
trol
syst
ems
and
crea
tesu
stai
ned
imba
lan
ces
and
elev
ated
leve
lsof
dise
ase-
rela
ted
Th
ere
sult
ing
mod
el,
calle
dth
eal
tern
ativ
eeq
uili
bria
(AE
)th
eory
,im
plie
sth
eex
iste
nce
ofan
expo
sure
thre
shol
dbe
low
wh
ich
tran
siti
onto
the
alte
rnat
ive
equ
ilibr
ium
(pot
enti
aldi
seas
e)
Th
ese
pred
icti
ons
may
hel
pto
expl
ain
patt
ern
sob
serv
edin
exp
erim
enta
lan
dep
idem
iolo
gica
lda
tafo
rdi
seas
essu
chas
CO
PD
,sili
cosi
s,an
din
flam
mat
ion
-med
iate
dlu
ng
can
cer
10 Arthritis
Ta
ble
2:C
onti
nu
ed.
vari
able
s,by
crea
tin
ga
new
,loc
ally
stab
le,a
lter
nat
ive
equ
ilibr
ium
for
the
dyn
amic
syst
em,i
nad
diti
onto
its
nor
mal
(hom
eost
atic
)eq
uili
briu
mSe
arch
stra
tegy
un
spec
ified
stat
ew
illn
otoc
cur,
and
once
exce
eded
,pr
ogre
ssio
nto
the
alte
rnat
ive
equ
ilibr
ium
con
tin
ues
spon
tan
eou
sly,
even
wit
hou
tfu
rth
erex
posu
re
Lin
dber
get
al.,
2011
CO
PD
[56]
Co-
mor
bidi
tyin
mild
-to-
mod
erat
eC
OP
D:c
ompa
riso
nto
nor
mal
and
rest
rict
ive
lun
gfu
nct
ion
Clin
ical
tria
lSu
bjec
tsw
ith
CO
PD
from
obst
ruct
ive
lun
gdi
seas
ein
nor
ther
nSw
eden
coh
ort
follo
wed
in20
02–2
004
(n=
993)
Gen
der
and
age
mat
ched
refe
ren
cesu
bjec
tsw
ith
out
CO
PD
(n=
993)
Toev
alu
ate
ifco
ndi
tion
sas
soci
ated
wit
hsy
stem
icin
flam
mat
ion
(e.g
.,ca
rdio
vasc
ula
rdi
seas
es,
diab
etes
,ch
ron
icrh
init
is,
and
gast
roes
oph
agea
lre
flu
x,ar
eov
erre
pres
ente
din
pati
ents
wit
hC
OP
DA
nal
ysis
base
don
inte
rvie
wda
taon
co-m
orbi
dity
and
sym
ptom
s
Pre
vale
nce
ofch
ron
icrh
init
isan
dga
stro
esop
hag
ealr
eflu
x(G
ER
D)
was
hig
her
inC
OP
Dco
mpa
red
tore
fere
nce
grou
pIn
rest
rict
ive
lun
gfu
nct
ion
,th
epr
eval
ence
ofch
ron
icrh
init
is,
card
iova
scu
lar
dise
ase,
hype
rlip
emia
,an
ddi
abet
esw
ash
igh
erco
mpa
red
tore
fere
nce
grou
pIn
CO
PD
and
hea
rtdi
seas
e,ch
ron
icrh
init
isan
d/or
GE
RD
wer
epr
opor
tion
atel
yh
igh
erth
anre
fere
nce
grou
p
Co-
mor
bid
con
diti
ons
asso
ciat
edw
ith
syst
emic
infl
amm
atio
n,f
orex
ampl
e,ca
rdio
vasc
ula
rdi
seas
e,ch
ron
icrh
init
is,
and
gast
roes
oph
agea
lre
flu
x,w
ere
com
mon
inpa
tien
tsw
ith
CO
PD
Ove
rlap
betw
een
hea
rtdi
seas
e,ch
ron
icrh
init
isan
dG
ER
Dw
asla
rge
inC
OP
D
ten
Hac
ken
,200
9P
roce
edin
gof
the
Am
eric
anT
hor
acic
Soci
ety
[57]
Phy
sica
lin
acti
vity
and
obes
ity:
rela
tion
toas
thm
aan
dch
ron
icob
stru
ctiv
epu
lmon
ary
dise
ase?
Rev
iew
Tosu
mm
ariz
eth
eav
aila
ble
liter
atu
rere
gard
ing
the
pote
nti
alro
leof
phys
ical
inac
tivi
tyan
dob
esit
yin
asth
ma
and
CO
PD
and
toex
amin
eth
eir
con
trib
uti
onto
syst
emic
infl
amm
atio
n
Phy
sica
lin
acti
vity
and
obes
ity
are
asso
ciat
edw
ith
low
-gra
desy
stem
icin
flam
mat
ion
that
may
con
trib
ute
toth
ein
flam
mat
ory
proc
esse
spr
esen
tin
man
ych
ron
icdi
seas
esSe
arch
stra
tegy
un
spec
ified
Hig
hpr
eval
ence
ofas
thm
ain
obes
ity
Inch
ron
icob
stru
ctiv
epu
lmon
ary
dise
ase
(CO
PD
),ph
ysic
alin
acti
vity
has
been
dem
onst
rate
dT
his
was
asso
ciat
edw
ith
ah
igh
erde
gree
ofsy
stem
icin
flam
mat
ion
,
Elu
cida
tion
ofth
ein
depe
nde
nt
rela
tion
ship
betw
een
phys
ical
inac
tivi
tyan
dob
esit
yw
ith
syst
emic
infl
amm
atio
n,
perf
orm
ance
-bas
edst
udi
esof
phys
ical
inac
tivi
tyin
asth
ma
and
CO
PD
are
nee
ded
Arthritis 11
Ta
ble
2:C
onti
nu
ed.
inde
pen
den
tof
body
mas
sin
dex
Obe
sity
isas
soci
ated
wit
hth
ech
ron
icob
stru
ctiv
eph
enot
ype
and
feat
ure
sof
the
met
abol
icsy
ndr
ome
Wou
ters
etal
.,20
09P
roce
edin
gsof
the
Am
eric
anT
hor
acic
Soci
ety
[58]
Syst
emic
and
loca
lin
flam
mat
ion
inas
thm
aan
dch
ron
icob
stru
ctiv
epu
lmon
ary
dise
ase:
isth
ere
aco
nn
ecti
on?
Rev
iew
Stat
e-of
-th
e-ar
t
Toex
amin
eth
eas
soci
atio
nbe
twee
nas
thm
aan
dch
ron
icob
stru
ctiv
epu
lmon
ary
dise
ase
(CO
PD
)Se
arch
stra
tegy
un
spec
ified
Spill
over
ofin
flam
mat
ory
med
iato
rsin
toth
eci
rcu
lati
onco
nsi
dere
dth
eso
urc
eof
syst
emic
infl
amm
atio
nin
thes
eco
ndi
tion
s
Nat
ure
ofsy
stem
icin
flam
mat
ion
rem
ain
su
ncl
ear
Adi
pose
tiss
ue
med
iate
din
flam
mat
ion
ison
eex
plan
atio
n
Dia
bete
sm
ellit
us
(typ
es1
and
2)
Ch
ang
etal
.,20
12in
pres
sA
cta
Dia
beto
logi
ca[5
9]
Acu
tean
dch
ron
icfl
uct
uat
ion
sin
bloo
dgl
uco
sele
vels
can
incr
ease
oxid
ativ
est
ress
inty
pe2
diab
etes
mel
litu
s
Clin
ical
tria
lSu
bjec
ts:p
atie
nts
wit
hty
pe2
diab
etes
mel
litu
s(n=
34)
Toex
amin
ew
het
her
shor
t-or
lon
g-te
rmgl
ycem
icfl
uct
uat
ion
sco
uld
indu
ceox
idat
ive
stre
ssan
dch
ron
icin
flam
mat
ion
,re
lati
onsh
ips
betw
een
glyc
emic
vari
abili
ty,
oxid
ativ
est
ress
mar
kers
,an
dh
igh
-sen
siti
vity
C-r
eact
ive
prot
ein
(hs-
CR
P)
wer
est
udi
ed
Rel
atio
nsh
ips
betw
een
mar
kers
for
shor
t-an
dlo
ng-
term
glyc
emic
con
trol
rem
ain
edsi
gnifi
can
tw
ith
resp
ect
toox
idat
ive
stre
ssan
dch
ron
icin
flam
mat
ion
,af
ter
adju
stin
gfo
rot
her
mar
kers
ofdi
abet
icco
ntr
ol
Bot
hac
ute
and
chro
nic
bloo
dgl
uco
seva
riab
ility
can
indu
ceox
idat
ive
stre
ssan
dch
ron
icin
flam
mat
ion
van
Bu
ssel
etal
.,20
12in
pres
sN
utr
itio
nan
dM
etab
olis
min
Car
diov
ascu
lar
Dis
ease
[60]
Un
hea
lthy
diet
ary
patt
ern
sas
soci
ated
wit
hin
flam
mat
ion
and
endo
thel
iald
ysfu
nct
ion
inty
pe1
diab
etes
:Th
eE
UR
OD
IAB
stu
dy
Clin
ical
tria
lTo
inve
stig
ate
the
asso
ciat
ion
betw
een
nu
trie
nt
con
sum
ptio
nan
dbi
omar
kers
ofen
doth
elia
ldys
fun
ctio
n(E
D)
and
low
-gra
dein
flam
mat
ion
(LG
I)in
subj
ects
wit
hty
pe1
diab
etes
(n=
491)
Ah
ealt
hydi
eth
asbe
enin
vers
ely
asso
ciat
edw
ith
ED
and
LGI
Nu
trie
nt
con
sum
ptio
nan
dlif
esty
leri
skfa
ctor
sw
ere
mea
sure
din
1989
and
1997
Bio
mar
kers
ofE
Dan
dLG
I(C
-rea
ctiv
epr
otei
n,
inte
rleu
kin
6,an
dtu
mou
rn
ecro
sis
fact
orα
)w
ere
mea
sure
din
Con
sum
ptio
nof
less
fibr
e,po
lyu
nsa
tura
ted
fat
and
vege
tabl
epr
otei
n,a
nd
mor
ech
oles
tero
love
rth
est
udy
per
iod
was
asso
ciat
edw
ith
mor
eE
Dan
dLG
I
Follo
win
gdi
etar
ygu
idel
ines
inty
pe
1di
abet
esm
ayre
duce
card
iova
scu
lar
dise
ase
risk
byfa
vou
rabl
yaff
ecti
ng
ED
and
LGI
12 Arthritis
Ta
ble
2:C
onti
nu
ed.
1997
and
aver
aged
into
Z-s
core
s.T
he
nu
trie
nt
resi
dual
met
hod
was
use
dto
adju
stin
divi
dual
nu
trie
nt
inta
kefo
ren
ergy
inta
keFi
brom
yalg
ia
Kad
etoff
etal
.,20
12Jo
urn
alof
Neu
roim
mu
nol
ogy
[61]
Evid
ence
ofce
ntr
alin
flam
mat
ion
infi
brom
yalg
ia-i
ncr
ease
dce
rebr
ospi
nal
flu
idin
terl
euki
n-8
leve
ls
Clin
ical
tria
lSu
bjec
ts:p
atie
nts
wit
hFM
Toas
sess
intr
ath
ecal
con
cen
trat
ion
sof
pro-
infl
amm
ator
ysu
bsta
nce
sin
pati
ents
wit
hFM
Ele
vate
dce
rebr
ospi
nal
flu
idan
dse
rum
con
cen
trat
ion
sof
inte
rleu
kin
-8,b
ut
not
inte
rleu
kin
-1be
ta,i
nFM
pati
ents
Fin
din
gsco
nsi
sten
tw
ith
ace
ntr
alpr
o-in
flam
mat
ory
com
pon
ent
Ort
ega
etal
.201
2Jo
urn
alof
Med
ical
Scie
nce
and
Spor
ts[6
2]
Aqu
atic
exer
cise
impr
oves
the
mon
ocyt
epr
o-an
dan
ti-i
nfl
amm
ator
ycy
toki
ne
prod
uct
ion
bala
nce
inpa
tien
tsw
ith
fibr
omya
lgia
(FM
)
Clin
ical
tria
lSu
bjec
ts:w
omen
pati
ents
wit
hFM
and
age-
mat
ched
con
trol
grou
pof
hea
lthy
wom
en
Eval
uat
edth
eeff
ect
ofa
pool
-aqu
atic
exer
cise
prog
ram
(8m
onth
s,tw
ow
eekl
y60
min
sess
ion
s)on
the
infl
amm
ator
ycy
toki
ne
prod
uct
ion
byis
olat
edm
onoc
ytes
,an
don
the
seru
mco
nce
ntr
atio
nof
C-r
eact
ive
prot
ein
(CR
P)
Mon
ocyt
esfr
omFM
pati
ents
rele
ased
mor
ein
flam
mat
ory
cyto
kin
esth
anth
ose
from
wom
enin
con
trol
grou
pFM
wom
enh
adh
igh
circ
ula
tin
gco
nce
ntr
atio
ns
ofC
RP
Incr
ease
dIL
-6w
ith
aco
nco
mit
ant
decr
ease
dT
NFα
spon
tan
eou
sre
leas
ew
asfo
un
daf
ter
4m
onth
sA
nti
-in
flam
mat
ory
effec
tof
the
exer
cise
prog
ram
was
also
corr
obor
ated
bya
decr
ease
inth
eci
rcu
lati
ng
CR
Pco
nce
ntr
atio
n
FMis
asso
ciat
edw
ith
chro
nic
infl
amm
atio
nth
atca
nbe
offse
tw
ith
phys
ical
exer
cise
such
asaq
uat
icex
erci
seE
xerc
ise
also
impr
oved
the
hea
lth
-rel
ated
qual
ity
oflif
eof
the
FMpa
tien
ts
Hyp
erte
nsi
on
Ber
nie
tal
.,20
12Jo
urn
alof
Hu
man
Hyp
erte
nsi
on[6
3]
Ren
alre
sist
ive
inde
xan
dlo
w-g
rade
infl
amm
atio
nin
pati
ents
wit
hes
sen
tial
hyp
erte
nsi
on
Clin
ical
tria
lSu
bjec
ts:h
yper
ten
sive
pati
ents
(n=
85;5
7±
14ye
ars,
61m
ales
)w
ith
out
diab
etes
,ren
al
Tost
udy
the
rela
tion
ship
betw
een
RR
Ian
dse
rum
hsC
RP
inhy
per
ten
sive
sw
ith
pres
erve
dre
nal
fun
ctio
n,w
ith
out
Pati
ents
wit
hpa
thol
ogic
RR
I(n=
21)
wer
eol
der
and
had
hig
her
hsC
RP
leve
lsco
mpa
red
wit
hpa
tien
tsw
ith
nor
mal
RR
I,as
wel
las
pati
ents
HsC
RP
isa
pred
icto
rof
both
path
olog
icR
RI
and
decr
ease
dR
V/R
RI,
even
afte
rad
just
men
tIn
esse
nti
alhy
per
ten
sion
,
Arthritis 13
Ta
ble
2:C
onti
nu
ed.
failu
re,
mic
roal
bum
inu
ria,
orm
ajor
infl
amm
ator
ydi
seas
e
mic
roal
bum
inu
ria
wit
hde
crea
sed
RV
/RR
I(n=
43)
HsC
RP
was
dire
ctly
rela
ted
wit
hR
RI
and
inve
rsel
yw
ith
RV
/RR
I
low
-gra
dein
flam
mat
ion
isas
soci
ated
wit
htu
bulo
inte
rsti
tial
dam
age
He
etal
.,20
12Jo
urn
alof
Hyp
erte
nsi
on[6
4]
Met
form
in-b
ased
trea
tmen
tfo
rob
esit
y-re
late
dhy
per
ten
sion
:ara
ndo
miz
ed,
dou
ble-
blin
d,pl
aceb
o-co
ntr
olle
dtr
ial
Ran
dom
ized
,do
ubl
e-bl
ind,
plac
ebo-
con
trol
led
tria
lSu
bjec
ts:p
arti
cipa
nts
ran
dom
ized
tom
etfo
rmin
(n=
180)
and
part
icip
ants
ran
dom
ized
topl
aceb
o(n=
180)
Toex
plor
ew
het
her
met
form
in-b
ased
trea
tmen
t(w
hic
hre
duce
sw
eigh
tan
din
flam
mat
ion
indi
abet
es)
ben
efits
obes
ity-
rela
ted
hyp
erte
nsi
onw
ith
out
diab
etes
24w
eek
dru
gtr
ial
Met
form
inco
mpa
red
wit
hpl
aceb
odi
dn
oth
ave
effec
tson
bloo
dpr
essu
re,b
lood
glu
cose
,an
dh
igh
-den
sity
orlo
w-d
ensi
tylip
opro
tein
chol
este
rol,
but
itdi
dre
duce
tota
lser
um
chol
este
rol
Met
form
inre
duce
dw
eigh
t,B
MI,
wai
stci
rcu
mfe
ren
cean
dbo
thsu
bcu
tan
eou
san
dvi
scer
alad
ipos
ity
and
low
ered
seru
mh
igh
-sen
siti
vity
C-r
eact
ive
prot
ein
Res
ult
ssu
ppor
ted
anin
flam
mat
ory
com
pon
ent
ofhy
pert
ensi
onin
pati
ent
wh
oar
eob
ese,
that
was
amen
able
tom
etfo
rmin
that
targ
ets
infl
amm
atio
n
Sari
etal
.201
1C
linic
alE
xper
imen
tal
Hyp
eten
sion
[65]
Th
eeff
ect
ofqu
inap
ril
trea
tmen
ton
insu
linre
sist
ance
,lep
tin
and
hig
hse
nsi
tive
C-r
eact
ive
prot
ein
inhy
per
ten
sive
pati
ents
Clin
ical
tria
lSu
bjec
ts:h
yper
ten
sive
pati
ents
(n=
54)
and
con
trol
subj
ects
(n=
24)
Toev
alu
ate
the
effec
tof
quin
apri
lon
HO
MA
-IR
,h
igh
sen
siti
veC
-rea
ctiv
epr
otei
n,a
nd
lept
inB
lood
pres
sure
,lep
tin
,hig
hse
nsi
tive
C-r
eact
ive
prot
ein
,an
dH
OM
A-I
Rw
ere
dete
rmin
edat
base
line
and
afte
r3
mon
ths
ofqu
inap
ril
trea
tmen
t
Aft
ertr
eatm
ent
wit
hqu
inap
rilH
OM
A-I
R,
hig
hse
nsi
tive
C-r
eact
ive
prot
ein
,an
dle
ptin
wer
ede
crea
sed
inhy
per
ten
sive
pati
ents
Qu
inap
rilm
aybe
use
das
ath
erap
yfo
rim
prov
ing
bloo
dpr
essu
reas
wel
las
the
insu
linre
sist
ant,
hyp
erle
ptin
emic
,an
dlo
w-g
rade
infl
amm
ator
yst
ate
inhy
per
ten
sion
Sugi
ura
etal
.201
1Jo
urn
alof
Clin
ical
Lipi
dolo
gy[6
6]
Impa
ctof
lipid
profi
lean
dh
igh
bloo
dpr
essu
reon
endo
thel
iald
amag
e
Clin
ical
tria
lJa
pan
ese
mal
eou
tpat
ien
tsw
ith
grad
eI
orII
hyp
erte
nsi
on,
Blo
odw
assa
mpl
edfo
rla
bora
tory
anal
ysis
and
endo
thel
ial
Tota
lch
oles
tero
lto
hig
h-d
ensi
tylip
opro
tein
chol
este
rolr
atio
Impa
ired
endo
thel
ial
fun
ctio
nw
asas
soci
ated
wit
hin
crea
sed
14 Arthritis
Ta
ble
2:C
onti
nu
ed.
alon
gw
ith
gen
der
and
age-
mat
ched
nor
mot
ensi
vesu
bjec
ts(b
othn=
25)
fun
ctio
nw
asas
sess
edby
flow
-med
iate
ddi
lati
on(F
MD
)
(tot
al-C
/HD
L-C
)w
asin
vers
ely
corr
elat
edw
ith
the
FMD
valu
ean
dpo
siti
vely
corr
elat
edw
ith
both
mal
ondi
alde
hyde
-m
odifi
edlo
w-d
ensi
tylip
opro
tein
and
hig
h-s
ensi
tivi
tyC
-rea
ctiv
epr
otei
nva
lues
toth
ose
inn
orm
oten
sive
subj
ects
wit
hh
igh
tota
l-C
/HD
L-C
tota
l-C
/HD
L-C
valu
es,
poss
ibly
asa
resu
ltof
incr
ease
dva
scu
lar
oxid
ativ
est
ress
and
infl
amm
atio
nIn
earl
yst
ages
ofat
her
oscl
eros
is,t
he
impa
ctof
both
tota
l-C
/HD
L-C
and
BP
may
besi
mila
rin
term
sof
endo
thel
iald
amag
e
Insu
linre
sist
ance
/met
abol
icsy
ndr
ome
Piy
aet
al.,
2006
inpr
ess
Jou
rnal
ofE
ndo
crin
olog
y[6
7]
Adi
poki
ne
infl
amm
atio
nan
din
sulin
resi
stan
ce:
the
role
ofgl
uco
se,l
ipid
san
den
doto
xin
Rev
iew
Toex
amin
eim
pact
ofn
utr
ien
tssu
chas
glu
cose
and
lipid
son
infl
amm
ator
ypa
thw
ays,
spec
ifica
llyw
ith
inad
ipos
eti
ssu
e,an
dh
owth
ese
infl
uen
cead
ipok
ine
infl
amm
atio
nan
din
sulin
resi
stan
ceSe
arch
stra
tegy
un
spec
ified
Th
rou
ghov
ern
utr
itio
n,
glu
cose
,lip
ids,
and
endo
toxi
naff
ect
diff
eren
tti
ssu
esto
med
iate
anab
erra
nt
infl
amm
ator
yre
spon
sean
dau
gmen
tpa
thog
enes
isof
insu
linre
sist
ance
and
met
abol
icdi
seas
e
Evid
ence
supp
orts
the
pers
iste
nt
insu
lts
from
dysf
un
ctio
nal
diet
sth
atn
eed
tobe
the
targ
ets
ofin
terv
enti
onR
edu
cin
gth
ebu
rden
inth
isw
aym
ayim
pact
peo
ple’
slo
ng-
term
hea
lth
Shoe
lson
etal
.,20
06Jo
urn
alof
Clin
ical
Inve
stig
atio
n[6
8]
Infl
amm
atio
nan
din
sulin
resi
stan
ceR
evie
w
Evid
ence
has
linke
din
flam
mat
ion
toth
epa
thog
enes
isof
type
2di
abet
es(T
2D)
Sear
chst
rate
gyu
nsp
ecifi
ed
Wit
hdi
scov
ery
ofan
impo
rtan
tro
lefo
rti
ssu
em
acro
phag
es,t
hes
efi
ndi
ngs
are
hel
pin
gto
resh
ape
thin
kin
gab
out
how
obes
ity
incr
ease
sth
eri
skfo
rT
2Dan
dm
etab
olic
syn
drom
e
Th
eev
olvi
ng
con
cept
ofin
sulin
resi
stan
cean
dT
2Das
hav
ing
imm
un
olog
ical
com
pon
ents
and
asim
prov
ing
the
pict
ure
ofh
owin
flam
mat
ion
mod
ula
tes
met
abol
ism
prov
ides
new
oppo
rtu
nit
ies
for
usi
ng
anti
-in
flam
mat
ory
stra
tegi
esto
addr
ess
met
abol
icco
nse
quen
ces
ofex
cess
adip
osit
y
Arthritis 15
Ta
ble
2:C
onti
nu
ed.
Isch
emic
hea
rtdi
seas
e
Sim
on,2
012
Cir
cula
tion
Jou
rnal
[69]
Infl
amm
atio
nan
dva
scu
lar
inju
ryR
evie
w
Toex
amin
eth
ece
ntr
alro
leof
infl
amm
atio
nin
vasc
ula
rin
jury
and
repa
irSe
arch
stra
tegy
un
spec
ified
Bin
din
gsi
tefo
rG
PIbα
inM
ac-1
show
sth
atle
uko
cyte
enga
gem
ent
ofpl
atel
etG
PIbα
via
Mac
-1is
crit
ical
for
the
biol
ogic
alre
spon
seto
vasc
ula
rin
jury
,th
rom
bosi
s,va
scu
litis
,gl
omer
ulo
nep
hri
tis,
and
mu
ltip
lesc
lero
sis
Alm
ost
alli
nfl
amm
atio
nis
plat
elet
depe
nde
nt
Lig
and
enga
gem
ent
ofM
ac-1
init
iate
sa
nov
elge
ne
that
prom
otes
infl
amm
atio
n
Kal
oger
opou
los
etal
.,20
12H
eart
Failu
reC
linic
s[7
0]
From
risk
fact
ors
tost
ruct
ura
lhea
rtdi
seas
e:th
ero
leof
infl
amm
atio
nR
evie
wR
evie
wst
rate
gyu
nsp
ecifi
ed
Ele
vate
dle
vels
ofci
rcu
lati
ng
proi
nfl
amm
ator
ycy
toki
nes
and
adip
okin
esh
ave
been
rep
eate
dly
asso
ciat
edw
ith
incr
ease
dri
skfo
rcl
inic
ally
man
ifes
t(S
tage
C)
hea
rtfa
ilure
inla
rge
coh
ort
stu
dies
.Th
ero
leof
low
-gra
de,s
ubc
linic
alin
flam
mat
ory
acti
vity
inth
etr
ansi
tion
from
risk
fact
ors
(Sta
geA
hea
rtfa
ilure
)to
stru
ctu
ral
hea
rtdi
seas
e(S
tage
Bh
eart
failu
re)
isle
ssw
ell
un
ders
tood
Rec
ent
evid
ence
sugg
ests
that
chro
nic
low
-gra
dein
flam
mat
ory
acti
vity
isin
volv
edin
mos
tm
ech
anis
ms
un
derl
yin
gpr
ogre
ssio
nof
stru
ctu
ral
hea
rtdi
seas
e,in
clu
din
gve
ntr
icu
lar
rem
odel
ing
afte
ris
chem
icin
jury
,re
spon
seto
pres
sure
and
volu
me
over
load
,an
dm
yoca
rdia
lfibr
osis
Infl
amm
atio
nal
soco
ntr
ibu
tes
topr
ogre
ssio
nof
per
iph
eral
vasc
ula
rch
ange
s
Viz
zard
iet
al.2
011
Pan
min
erva
Med
ica
[71]
Hel
icob
acto
rpy
lori
and
isch
emic
hea
rtdi
seas
eR
evie
w
Man
yst
udi
esh
ave
been
perf
orm
edon
the
rela
tion
ship
betw
een
infe
ctio
nfr
omH
elic
obac
ter
pylo
rian
dat
her
oscl
erot
icdi
seas
es,l
ike
stro
kean
dis
chem
ich
eart
dise
ase
Rev
iew
ofth
elit
erat
ure
that
has
inve
stig
ated
the
role
ofH
Pin
the
deve
lopm
ent
and
path
ogen
esis
ofC
AD
.In
fect
ion
cou
ldle
adto
IHD
thro
ugh
path
way
ssu
chas
endo
thel
ialc
ells
Res
ult
sfr
omth
ese
stu
dies
hav
era
ised
new
per
spec
tive
son
coro
nar
yh
eart
dise
ase,
esp
ecia
llyre
gard
ing
the
pos
sibi
lity
ofm
odif
yin
gth
ecl
inic
alh
isto
ryof
the
dise
ase
thro
ugh
erad
icat
ion
ofth
ese
16 Arthritis
Ta
ble
2:C
onti
nu
ed.
Som
ein
fect
ion
sco
uld
hav
ea
role
onth
ege
nes
isan
dde
velo
pmen
tof
dam
age
toth
eva
scu
lar
wal
lan
dof
ath
erom
atou
spl
aqu
eH
Pco
uld
infl
uen
ceth
ede
velo
pmen
tof
IHD
thro
ugh
vari
ous
path
way
sSe
arch
stra
tegy
un
spec
ified
colo
niz
atio
n,c
han
ges
inth
elip
idpr
ofile
s,in
crea
sed
coag
ula
tion
and
plat
elet
aggr
egat
ion
leve
ls,i
ndu
ctio
nof
mol
ecu
lar
mim
icry
mec
han
ism
s,an
dth
epr
omot
ion
ofa
low
-gra
desy
stem
icin
flam
mat
ion
infe
ctiv
em
icro
orga
nis
ms
Furt
her
stu
dies
indi
cate
d
Kid
ney
dise
ase
Kan
get
al.,
2012
Jou
rnal
ofK
orea
nM
edic
alSc
ien
ce[7
2]
Low
-gra
dein
flam
mat
ion
,met
abol
icsy
ndr
ome
and
the
risk
ofch
ron
icki
dney
dise
ase:
a20
05K
orea
nN
atio
nal
Hea
lth
and
Nu
trit
ion
Exa
min
atio
nSu
rvey
Cro
ss-s
ecti
onal
stu
dySu
bjec
ts:a
dult
sre
gist
ered
inth
en
atio
nal
surv
ey(n=
5291
)
Toex
amin
eth
ere
lati
onsh
ipbe
twee
nw
hit
ebl
ood
cell
(WB
C)
cou
nt
and
chro
nic
kidn
eydi
seas
e≥s
tage
3M
easu
res
ofgl
omer
ula
rfi
ltra
tion
rate
s
Low
-gra
dein
flam
mat
ion
isas
soci
ated
wit
hch
ron
icki
dney
dise
ase
inp
eopl
ew
ith
met
abol
icsy
ndr
ome≥s
tage
3
Low
-gra
dein
flam
mat
ion
asso
ciat
edw
ith
chro
nic
kidn
eydi
seas
e≥s
tage
3in
peo
ple
wit
hm
etab
olic
syn
drom
esu
gges
tsn
ewtr
eatm
ent
appr
oach
es
Koc
yigi
tet
al.,
2012
Am
eric
anJo
urn
alof
Nep
hro
logy
[73]
Ear
lyar
teri
alst
iffn
ess
and
infl
amm
ator
ybi
o-m
arke
rsin
nor
mot
ensi
vepo
lycy
stic
kidn
eydi
seas
epa
tien
ts
Clin
ical
tria
lC
ross
-sec
tion
alde
sign
Pati
ents
(n=
50)
wit
hau
toso
mal
-dom
inan
tki
dney
dise
ase
(AD
PK
D)
(42%
mal
es,3
6.6±
9.9
year
s,n
obl
ood
pres
sure
med
icat
ion
)an
dh
ealt
hyco
ntr
ols
(n=
50)
(44%
mal
es,3
5.4±
6.4
year
s)
Tocl
arif
yte
mpo
ral
rela
tion
ship
betw
een
AD
PK
D,h
yper
ten
sion
,an
dth
elo
ssof
ren
alfu
nct
ion
,pa
tien
tsw
ith
earl
y-st
age
AD
PK
Dw
ho
did
not
yet
hav
ehy
pert
ensi
onw
ere
exam
ined
Pu
lse
wav
eve
loci
ty(P
WV
),ca
rdia
cm
orph
olog
yan
dfu
nct
ion
,aor
tic
elas
tic
inde
xes,
esti
mat
edgl
omer
ula
rfi
ltra
tion
rate
(eG
FR),
24-h
our
ambu
lato
rybl
ood
pres
sure
,in
terl
euki
n-6
(IL-
6),t
um
orn
ecro
sis
fact
or-α
(TN
F-α
),an
dh
igh
lyse
nsi
tive
C-r
eact
ive
prot
ein
(hs-
CR
P)
wer
em
easu
red
Des
pite
nor
mal
bloo
dpr
essu
re,a
orti
cst
iffn
ess
inde
xan
dpu
lse
wav
eve
loci
tyva
lues
wer
ein
crea
sed
inpa
tien
tsco
mpa
red
toco
ntr
ols
Inu
niv
aria
tean
alys
is,
IL-6
,TN
F-α
,hs-
CR
P,an
deG
FRw
ere
corr
elat
edw
ith
PW
VP
WV
ispr
edic
ted
byIL
-6,T
NF-α
,an
dh
s-C
RP
Incr
ease
dar
teri
alst
iffn
ess
and
puls
ew
ave
velo
city
are
earl
ym
anif
esta
tion
sof
AD
PK
Dap
pea
rin
gbe
fore
hyp
erte
nsi
onor
redu
ced
eGFR
Th
ese
vasc
ula
rab
nor
mal
itie
sar
ere
late
dto
sign
sof
syst
emic
low
grad
ein
flam
mat
ion
Fin
din
gssu
ppor
ta
com
mon
path
ophy
siol
ogic
alm
ech
anis
map
pare
ntl
ypr
esen
tal
soin
oth
erva
scu
lar
dise
ases
Arthritis 17
Ta
ble
2:C
onti
nu
ed.
Luis
-R
odrı
guez
etal
.,20
12W
orld
Jou
rnal
ofD
iabe
tes
[74]
Path
ophy
siol
ogic
alro
lean
dth
erap
euti
cim
plic
atio
ns
ofin
flam
mat
ion
indi
abet
icn
eph
ropa
thy
Rev
iew
(exp
erim
enta
lan
dcl
inic
alst
udi
es)
Toid
enti
fypa
thog
enic
path
way
sfo
rea
rlie
rdi
agn
osis
and
targ
etin
gn
ovel
trea
tmen
tsSe
arch
stra
tegy
un
spec
ified
Act
ivat
ion
ofin
nat
eim
mu
nit
yw
ith
deve
lopm
ent
ofa
chro
nic
low
grad
ein
flam
mat
ory
resp
onse
isa
reco
gniz
edfa
ctor
inth
epa
thog
enes
isof
diab
etic
nep
hro
path
yE
xper
imen
tala
nd
clin
ical
stu
dies
supp
ort
vari
ous
infl
amm
ator
ym
olec
ule
san
dpa
thw
ays
inth
epa
thoe
tiol
ogy
ofdi
abet
icn
euro
path
y
Incr
ease
dkn
owle
dge
and
un
ders
tan
din
gof
infl
amm
ator
ym
ech
anis
ms
are
nee
ded
toau
gmen
tcl
inic
alin
terv
enti
ons
for
this
com
plic
atio
n
Tan
get
al.,
2012
Inte
rnat
ion
alJo
urn
alof
Nep
hro
logy
[75]
Infl
amm
atio
nan
dox
idat
ive
stre
ssin
obes
ity-
rela
ted
glom
eru
lopa
thy
Rev
iew
Tofo
cus
onin
flam
mat
ion
and
oxid
ativ
est
ress
inth
epr
ogre
ssio
nof
obes
ity-
rela
ted
glom
eru
lopa
thy
and
poss
ible
inte
rven
tion
sto
prev
ent
kidn
eyin
jury
inob
esit
ySe
arch
stra
tegy
un
spec
ified
Obe
sity
-rel
ated
glom
eru
lopa
thy
isa
maj
orca
use
ofen
d-st
age
ren
aldi
seas
e.O
besi
tyh
asbe
enco
nsi
dere
da
stat
eof
chro
nic
low
-gra
desy
stem
icin
flam
mat
ion
and
chro
nic
oxid
ativ
est
ress
Au
gmen
ted
infl
amm
atio
nin
adip
ose
and
kidn
eyti
ssu
espr
omot
esth
epr
ogre
ssio
nof
kidn
eyda
mag
ein
obes
ity
Adi
pose
tiss
ue,
wh
ich
isac
cum
ula
ted
inob
esit
y,is
ake
yen
docr
ine
orga
nth
atpr
odu
ces
mu
ltip
lebi
olog
ical
lyac
tive
mol
ecu
les,
incl
udi
ng
lept
in,a
dipo
nec
tin
,an
dre
sist
in,t
hat
affec
tin
flam
mat
ion
Oxi
dati
vest
ress
isal
soas
soci
ated
wit
hob
esit
y-re
late
dre
nal
dise
ases
and
may
trig
ger
the
init
iati
onor
prog
ress
ion
ofre
nal
dam
age
inob
esit
yB
oth
infl
amm
atio
nan
dox
idat
ive
stre
ssin
duce
dam
age
tore
nal
tubu
lean
dgl
omer
ulu
san
dre
sult
inen
doth
elia
ldy
sfu
nct
ion
inth
eki
dney
An
ti-i
nfl
amm
atio
nan
dan
tiox
idan
t
18 Arthritis
Ta
ble
2:C
onti
nu
ed.
inte
rven
tion
sm
aybe
ther
apie
sto
prev
ent
and
trea
tob
esit
y-re
late
dre
nal
dise
ases
Obe
sity
Hu
lsm
ans
etal
.,20
12P
LoS
On
e[7
6]
Inte
rleu
kin
-1re
cept
or-a
ssoc
iate
dki
nas
e-3
isa
key
inh
ibit
orof
infl
amm
atio
nin
obes
ity
and
met
abol
icsy
ndr
ome
Exp
erim
enta
lan
dcl
inic
alst
udi
esO
bese
indi
vidu
als
(n=
21an
d10
2)an
dag
e-m
atch
edco
ntr
ols
(n=
46)
Clu
ster
ofm
olec
ule
sw
ere
stu
died
that
supp
ort
inte
ract
ion
sbe
twee
nth
est
ress
con
diti
ons
oflo
w-g
rade
infl
amm
atio
nan
dox
idat
ive
stre
ssin
mon
ocyt
esE
ffec
tof
thre
em
onth
wei
ght
loss
afte
rba
riat
ric
surg
ery
exam
ined
Vis
cera
lobe
sity
isas
soci
ated
wit
hty
pe2
diab
etes
and
met
abol
icsy
ndr
ome
Low
-gra
dech
ron
icin
flam
mat
ion
and
oxid
ativ
est
ress
syn
ergi
zein
obes
ity
and
obes
ity-
indu
ced
diso
rder
sO
dds
rati
oof
hig
h-s
ensi
tivi
tyC
-rea
ctiv
epr
otei
n,a
wid
ely
use
dm
arke
rof
syst
emic
infl
amm
atio
n,
was
4.3
Wei
ght
loss
was
wit
ha
low
erin
gof
syst
emic
infl
amm
atio
nan
da
decr
easi
ng
nu
mbe
rof
met
abol
icsy
ndr
ome
com
pon
ents
An
incr
ease
inre
acti
veox
ygen
spec
ies
inco
mbi
nat
ion
wit
hob
esit
y-as
soci
ated
low
adip
onec
tin
and
hig
hgl
uco
sean
din
terl
euki
n-6
was
iden
tifi
edas
the
cau
seof
the
decr
ease
inIR
AK
3in
TH
P-1
cells
invi
tro
Issa
and
Gri
ffin
,201
2Pa
thob
iolo
gyof
Agi
ng
and
Age
Rel
ated
Dis
ease
s[8
]
Path
obio
logy
ofob
esit
yan
dos
teoa
rth
riti
s:in
tegr
atin
gbi
omec
han
ics
and
infl
amm
atio
n
Rev
iew
Sear
chst
rate
gyu
nsp
ecifi
ed
Path
obio
logy
ofob
esit
yan
dos
teoa
rth
riti
s(O
A)
was
exam
ined
,as
wel
las
liter
atu
reth
eu
nde
rlyi
ng
syst
emic
infl
amm
atio
n,
its
rela
tion
ship
toin
acti
vity
,an
dth
eir
inte
ract
ion
s
Infl
amm
atio
nis
cen
tral
topr
ogre
ssio
nof
the
dise
ase
cycl
ein
volv
ing
obes
ity,
oste
oart
hri
tis,
and
phys
ical
inac
tivi
tyM
etab
olic
infl
amm
atio
nis
belie
ved
toco
ntr
ibu
teto
met
abol
icin
flex
ibili
tyan
don
-goi
ng
prod
uct
ion
ofpr
o-in
flam
mat
ory
med
iato
rsFi
ndi
ngs
supp
ort
that
met
abol
icin
flam
mat
ion
incr
ease
sO
Ari
sk
Arthritis 19
Ta
ble
2:C
onti
nu
ed.
Ric
o-R
osill
oan
dV
ega-
Rob
ledo
,201
2R
evis
taM
edic
ade
lIn
stit
uto
Mex
ican
ode
lSe
guro
Soci
al[7
7]
New
tren
dsin
mac
roph
ages
,in
flam
mat
ion
and
adip
ose
tiss
ue
Rev
iew
Toh
igh
ligh
tth
em
acro
phag
epa
rtic
ipat
ion
inth
ege
ner
atio
nof
obes
ity-
indu
ced
infl
amm
atio
nSe
arch
stra
tegy
un
spec
ified
Acc
um
ula
tin
gev
iden
cesu
gges
tth
ein
volv
emen
tof
adip
ose
tiss
ue
deri
ved
prot
ein
s,co
llect
ivel
ykn
own
asad
ipok
ines
asw
ella
sot
her
fact
ors
prod
uce
din
this
tiss
ue
byce
llsbe
side
sad
ipoc
ytes
,lik
efi
brob
last
s,ly
mph
ocyt
es,
and
mac
roph
ages
Obe
sity
burd
enon
hea
lth
exte
nds
acro
ssm
ult
iple
orga
ns
syst
ems
and
dise
ases
(ath
eros
cler
osis
,co
ron
ary
hea
rtdi
seas
es,
oste
oart
hri
tis,
diab
etes
,hy
per
ten
sion
,an
ddy
slip
idem
ia)
Obe
sity
isco
nsi
dere
da
low
-in
flam
mat
ory
con
diti
onA
nin
crea
sin
gn
um
ber
ofre
port
ssu
gges
tth
atth
ead
ipos
eti
ssu
eit
self
mig
ht
bea
sou
rce
ofpr
o-in
flam
mat
ory
fact
ors
and
ata
rget
ofin
flam
mat
ory
proc
esse
sEv
iden
cesu
ppor
tsin
volv
emen
tof
adip
ose
tiss
ue-
deri
ved
prot
ein
s,co
llect
ivel
ykn
own
asad
ipok
ines
and
oth
erfa
ctor
spr
odu
ced
inth
isti
ssu
eby
cells
besi
des
adip
ocyt
es(fi
brob
last
s,ly
mph
ocyt
es,a
nd
mac
roph
ages
)
Stie
nst
ra,2
007
PPA
RR
esea
rch
[78]
PPA
Rs,
obes
ity,
and
infl
amm
atio
nR
evie
w
Toad
dres
sth
ero
leof
pero
xiso
me
prol
ifer
ator
-act
ivat
orre
cept
ors
(PPA
Rs)
inob
esit
y-in
duce
din
flam
mat
ion
spec
ifica
llyin
adip
ose
tiss
ue,
liver
,an
dth
eva
scu
lar
wal
lSe
arch
stra
tegy
un
spec
ified
Ch
ange
sin
infl
amm
ator
yst
atu
sof
adip
ose
tiss
ue
and
liver
wit
hob
esit
ysu
ppor
tsco
-exi
sten
tch
ron
iclo
w-l
evel
infl
amm
atio
nV
ario
us
mol
ecu
lar
mec
han
ism
sh
ave
been
impl
icat
edin
obes
ity-
indu
ced
infl
amm
atio
n(s
ome
mod
ula
ted
byP
PAR
s)P
PAR
sm
odu
late
the
infl
amm
ator
yre
spon
se,
hen
ce,c
onst
itu
tea
ther
apeu
tic
targ
etto
mit
igat
eob
esit
y-in
duce
din
flam
mat
ion
and
its
con
sequ
ence
s
Obe
sity
isac
com
pan
ied
wit
hfa
tst
orag
ein
tiss
ues
oth
erth
anad
ipos
eti
ssu
e(l
iver
and
skel
etal
mu
scle
)w
hic
hm
ayle
adto
loca
lin
sulin
resi
stan
cean
dst
imu
late
infl
amm
atio
nO
besi
tych
ange
sth
em
orph
olog
yan
dco
mpo
siti
onof
adip
ose
tiss
ue,
lead
ing
toch
ange
sin
its
prot
ein
prod
uct
ion
and
secr
etio
nin
clu
din
gpr
o-in
flam
mat
ory
med
iato
rs
20 Arthritis
Ta
ble
2:C
onti
nu
ed.
Tajik
etal
.201
2in
pres
sJo
urn
alof
En
docr
inol
ogic
alIn
vest
igat
ion
[79]
Eff
ect
ofdi
et-i
ndu
ced
wei
ght
loss
onin
flam
mat
ory
cyto
kin
esin
obes
ew
omen
Clin
ical
tria
lSu
bjec
ts:P
rem
enop
ausa
lob
ese
wom
en(b
ody
mas
sin
dex≥
30)
aged
21to
54ye
ars
wit
hou
tdi
abet
es,h
yper
ten
sion
,or
hype
rlip
idem
ia(n=
29)
Toev
alu
ate
chan
ges
inpr
o/an
ti-i
nfl
amm
ator
yad
ipoc
ytok
ines
and
met
abol
icpr
ofile
afte
rm
oder
ate
diet
-in
duce
dw
eigh
t,an
thro
pom
etri
cpa
ram
eter
s,lip
idan
dgl
uco
sepr
ofile
s,IL
-6,
IL-1
0,an
dIL
-18
wer
em
easu
red
Subj
ects
then
ente
red
into
aw
eigh
tre
duct
ion
prog
ram
(3m
onth
s)
Bod
ym
ass
inde
x,w
aist
circ
um
fere
nce
,tri
ceps
skin
fold
thic
knes
s,to
tal
chol
este
rol,
trig
lyce
ride
,an
dfa
stin
gpl
asm
agl
uco
sede
crea
sed,
wh
ileH
DL-
chol
este
rol
incr
ease
dW
hile
plas
ma
leve
lsof
IL-6
and
IL-1
8de
crea
sed,
no
chan
gew
asob
serv
edin
circ
ula
tin
gle
vels
ofIL
-10
Obe
sity
isas
soci
ated
wit
hlo
w-g
rade
syst
emic
infl
amm
atio
nw
hic
hh
asbe
enlin
ked
toth
ein
crea
sed
risk
ofca
rdio
vasc
ula
rdi
seas
ean
dty
pe
IIdi
abet
esin
obes
epa
tien
tsim
prov
edbo
dyco
mpo
siti
onin
duce
dby
rest
rict
ion
ofen
ergy
inta
keis
asso
ciat
edw
ith
favo
rabl
ese
rum
con
cen
trat
ion
sof
IL-6
and
IL-1
8in
obes
ew
omen
Rh
eum
atoi
dar
thri
tis
Gre
mes
ean
dFe
rrac
ciol
i20
11A
uto
imm
un
olog
yR
evie
w[8
0]
Th
em
etab
olic
syn
drom
e:th
ecr
ossr
oads
betw
een
rheu
mat
oid
arth
riti
san
dca
rdio
vasc
ula
rri
sk
Rev
iew
Rh
eum
atoi
dar
thri
tis
(RA
)pa
tien
tsh
ave
anin
cide
nce
ofca
rdio
vasc
ula
r(C
V)
dise
ases
two-
fold
that
ofth
ege
ner
alpo
pula
tion
Ath
eros
cler
osis
,th
em
ain
dete
rmin
ant
ofC
Vm
orbi
dity
and
mor
talit
y,an
dca
roti
din
tim
a-m
edia
thic
knes
s,an
earl
ypr
eclin
ical
mar
ker
ofat
her
oscl
eros
is,a
lso
occu
rea
rly
onin
RA
Sear
chst
rate
gyu
nsp
ecifi
ed
CV
risk
fact
ors
seem
toh
ave
the
sam
epr
eval
ence
inR
Aan
dn
on-R
Apa
tien
ts,t
hus
they
don
otfu
llyex
plai
nin
crea
sed
CV
burd
en,
sugg
esti
ng
that
RA
infl
amm
atio
nan
dth
erap
ies
play
aro
lein
incr
easi
ng
CV
risk
inth
ese
pati
ents
Th
em
etab
olic
syn
drom
e(M
etS)
and
fat
tiss
ue
are
likel
ym
ajor
play
ers
inth
isco
mpl
exn
etw
ork
Th
eas
soci
atio
nof
Met
San
dat
her
oscl
eros
isis
part
lym
edia
ted
byal
tere
dse
cret
ion
ofad
ipok
ines
byad
ipos
eti
ssu
ean
d,
Obe
sity
isn
owre
gard
edas
asy
stem
ic,l
ow-g
rade
infl
amm
ator
yst
ate,
and
infl
amm
atio
nas
alin
kbe
twee
nob
esit
y,m
etab
olic
syn
drom
e,an
dC
Vdi
seas
esTo
con
trol
CV
risk
,dat
asu
ppor
tth
en
eces
sity
of“t
igh
tco
ntr
ol”
ofin
flam
mat
ion
from
both
RA
and
Met
S
Arthritis 21
Ta
ble
2:C
onti
nu
ed.
onth
eot
her
han
d,th
ere
are
evid
ence
that
adip
okin
esm
aypl
aya
role
inin
flam
mat
ory
RA
Pre
teet
al.,
2011
Au
toim
mu
nol
ogy
Rev
iew
[81]
Ext
ra-a
rtic
ula
rm
anif
esta
tion
sof
rheu
mat
oid
arth
riti
s:A
nu
pdat
e
Rev
iew
Rh
eum
atoi
dar
thri
tis
(RA
)is
anim
mu
ne-
med
iate
ddi
seas
ein
volv
ing
chro
nic
low
-gra
dein
flam
mat
ion
that
may
prog
ress
ivel
yle
adto
join
tde
stru
ctio
n,
defo
rmit
y,di
sabi
lity,
and
even
deat
hD
espi
teit
spr
edom
inan
tos
teoa
rtic
ula
ran
dp
eria
rtic
ula
rm
anif
esta
tion
s,R
Ais
asy
stem
icdi
seas
eof
ten
asso
ciat
edw
ith
cuta
neo
us
and
orga
n-s
peci
fic
extr
a-ar
ticu
lar
man
ifes
tati
ons
(EA
M)
Cu
rren
tR
evie
ws
know
ledg
eab
out
EA
Min
term
sof
freq
uen
cy,c
linic
alas
pec
ts,a
nd
curr
ent
ther
apeu
tic
appr
oach
es.I
nan
init
iala
ttem
ptat
acl
assi
fica
tion
,we
sepa
rate
dE
AM
from
RA
co-m
orbi
diti
esan
dfr
omge
ner
al,c
onst
itu
tion
alm
anif
esta
tion
sof
syst
emic
infl
amm
atio
n.E
AM
was
clas
sifi
edas
cuta
neo
us
and
visc
eral
form
s,bo
thse
vere
and
not
seve
reSe
arch
stra
tegy
un
spec
ified
Inag
greg
ated
data
from
12la
rge
RA
coh
orts
,pa
tien
tsw
ith
EA
M,
esp
ecia
llyth
ese
vere
form
s,w
ere
fou
nd
toh
ave
grea
ter
co-m
orbi
dity
and
mor
talit
yth
anpa
tien
tsw
ith
out
EA
M
Un
ders
tan
din
gth
eco
mpl
exit
yof
EA
Man
dth
eir
man
agem
ent
rem
ain
sa
chal
len
gefo
rcl
inic
ian
s,es
peci
ally
sin
ceth
eeff
ecti
ven
ess
ofdr
ug
ther
apy
onE
AM
awai
tsst
udy
Stro
ke
Den
eset
al.2
011
Cer
ebro
vasc
ula
rD
isea
se[8
2]
Inte
rleu
kin
-1an
dst
roke
:bi
omar
ker,
har
bin
ger
ofda
mag
e,an
dth
erap
euti
cta
rget
Rev
iew
Infl
amm
atio
nis
esta
blis
hed
asa
con
trib
uto
rto
cere
brov
ascu
lar
dise
ase
Ris
kfa
ctor
sfo
rst
roke
incl
ude
man
yco
ndi
tion
sas
soci
ated
wit
hch
ron
icor
acu
tein
flam
mat
ion
,an
din
flam
mat
ory
chan
ges
inth
ebr
ain
afte
rce
rebr
ovas
cula
rev
ents
con
trib
ute
Evid
ence
supp
orts
impo
rtan
ceof
per
iph
eral
ly-d
eriv
edim
mu
ne
cells
and
infl
amm
ator
ym
olec
ule
sin
vari
ous
cen
tral
ner
vou
ssy
stem
diso
rder
s,in
clu
din
gst
roke
Infl
amm
ator
ycy
toki
ne,
inte
rleu
kin
-1(I
L-1)
,pl
ays
api
vota
lrol
ein
both
loca
lan
dsy
stem
ic
Blo
ckad
eof
IL-1
cou
ldbe
ther
apeu
tica
llyu
sefu
lin
seve
rald
isea
ses
wh
ich
are
risk
fact
ors
for
stro
keT
her
eis
con
side
rabl
epr
eclin
ical
and
clin
ical
evid
ence
that
inh
ibit
ion
ofIL
-1by
IL-1
rece
ptor
anta
gon
ist
may
beva
luab
lein
the
man
agem
ent
ofac
ute
stro
ke
22 Arthritis
Ta
ble
2:C
onti
nu
ed.
toou
tcom
ein
exp
erim
enta
lst
udi
es,w
ith
grow
ing
evid
ence
from
clin
ical
rese
arch
Sear
chst
rate
gyu
nsp
ecifi
ed
infl
amm
atio
nan
dis
ake
ydr
iver
ofp
erip
hera
lan
dce
ntr
alim
mu
ne
resp
onse
sto
infe
ctio
nor
inju
ry
Wu
etal
.,20
12A
mer
ican
Jou
rnal
ofR
hin
olog
ical
Alle
rgy
[83]
Ris
kof
stro
keam
ong
pati
ents
wit
hrh
inos
inu
siti
s:a
popu
lati
on-b
ased
stu
dyin
Taiw
an
Popu
lati
on-b
ased
tria
lP
rosp
ecti
veco
hor
tst
udy
Pati
ents
inTa
iwan
(Lon
gitu
din
alH
ealt
hIn
sura
nce
Dat
abas
e20
05(L
HID
2005
))w
ho
had
rece
ived
adi
agn
osis
ofrh
inos
inu
siti
s(n=
53,6
53)
betw
een
Jan
uar
y1,
2004
and
Dec
embe
r31
,200
5C
ontr
olgr
oup
(1:4
)dr
awn
from
the
sam
eda
taba
sew
asm
atch
edfo
rag
ean
dge
nde
r(n=
214,
624)
Eac
hpa
tien
tw
asfo
llow
edu
pu
sin
gda
taen
tere
du
nti
lth
een
dof
2006
Pro
port
ion
alh
azar
dre
gres
sion
sw
ere
per
form
edto
eval
uat
eth
eh
azar
dra
tios
(HR
s)af
ter
adju
stin
gfo
rpo
ten
tial
con
fou
ndi
ng
fact
ors
Pati
ents
wit
hrh
inos
inu
siti
sw
ere
mor
elik
ely
tosu
ffer
stro
kes
than
the
con
trol
popu
lati
on,a
fter
adju
stin
gfo
rp
oten
tial
con
fou
nde
rs
Bot
hac
ute
and
chro
nic
sin
usi
tis
are
risk
fact
ors
orm
arke
rsfo
rst
roke
that
isin
depe
nde
nt
oftr
adit
ion
alst
roke
risk
fact
ors
Furt
her
epid
emio
logi
cal
rese
arch
isw
arra
nte
d
Arthritis 23
Table 3: Pro- and anti-inflammatory foods (Source: [85–87]).
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 irritationCooking 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 waterDairyLow-fat milk products are acceptable particularly plainyogurt, 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 beenexemplified than in an elegant but simple study reported byFord and colleagues [95]. In their study of over 23,000 peoplebetween 35 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 kg·m2; 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
24 Arthritis
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, andprescribed 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 thepatient’s 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 [96–99].
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 [100–102]. In addition, the 5’s 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 thepatient’s signs and symptoms. In addition to integratingdietary 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 withosteoarthritis. 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 farreaching 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
Arthritis 25
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 patient’sinflammatory threshold, reducing rate of disease progres-sion, reducing weight, and maximizing health by minimizinga patient’s 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 patient’s 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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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Oxidative Medicine and Cellular Longevity
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PPAR Research
The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014
Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
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ObesityJournal of
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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014
Research and TreatmentAIDS
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Gastroenterology Research and Practice
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Parkinson’s Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com