Rheumatoid Arthritis

180 Pages·2015·5.43 MB·English

SeminarsinArthritisandRheumatism43(2014)479–488
ContentslistsavailableatScienceDirect
Seminars in Arthritis and Rheumatism
journal homepage: www.elsevier.com/locate/semarthrit
Burden of disease in treated rheumatoid arthritis patients: Going
beyond the joint
Maurizio Cutolo, MDa,n, George D. Kitas, MD, PhD, FRCPb, Piet L.C.M. van Riel, MD, PhDc
aResearchLaboratoriesandAcademicDivisionofClinicalRheumatology,DepartmentofInternalMedicine,UniversityofGenoa,VialeBenedettoXV6,Genoa
16132,Italy
bClinicalRheumatologyandR&DDirector,DepartmentofRheumatology,DudleyGroupNHSFoundationTrust,Dudley,UnitedKingdom;andArthritis
ResearchUKEpidemiologyUnit,UniversityofManchester,Manchester,UK
cRheumatology,DepartmentofRheumatology,RadboudUniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands
a b s t r a c t
Objective: The disease burden in rheumatoid arthritis (RA) extends beyond the joint. This article
evaluatesthephysicalandpsychosocialextra-articular burdenof treatedRAandrelationshipsamong
diversediseasemanifestations.
Methods: MEDLINEsearchesidentifiedpaperspublishedinEnglishfromJanuary2003toDecember2012
that evaluated systemic complications and psychosocial aspects associated with RA. Preference was
giventostudieswithrandomizedcohortsandlarge(4100)samplesizes.Of378articlesidentifiedinthe
initialsearch,118wereselectedforinclusion.
Results: RAisassociatedwithmultiplecomorbiditiesandpsychosocialimpairments,includingcardio-
vascular disease, osteoporosis, interstitial lung disease, infection, malignancies, fatigue, depression,
cognitivedysfunction,reducedworkperformance,workdisability,anddecreasedhealth-relatedquality
oflife.Theetiologyof theextra-articular burdenmayreflectthesystemicinflammation andimmune
systemalterationassociatedwithRA,metabolicimbalancesandsideeffectsrelatedtotreatment,orthe
influenceofcomorbidities.Strategiesthatmayhelptoreducetheextra-articulardiseaseburdeninclude
personalizedmedicineandthepotentialintroductionoftreatmentswithnewmechanismsofaction.
Conclusion: Despite improvements in treating joint disease, the extra-articular burden in RA remains
substantial,encompassingmultiplecomorbiditiesandpsychosocialimpairments.
&2014ElsevierInc.Allrightsreserved.
Introduction College of Rheumatology (ACR) provide algorithms for the use of
synthetic disease-modifying antirheumatic drugs (DMARDs) and
Rheumatoid arthritis (RA) is an inflammatory, immune- biologics [4,5]. Pharmacotherapies are started at the time of RA
mediated disease with a prevalence of 0.5–1% in developed diagnosis,withthegoalofachievingclinicalremissionor,ifthatis
countries [1,2]. In RA, chronic synovial inflammation and hyper- not possible, low disease activity. Specific treatment choices are
plasia drive articular destruction and bone erosion, leading to guidedbydiseaseactivityandprognosticfeatures.
functional decline and disability [3]. The treatment paradigm for With this therapeutic approach, most patients can be treated
RA has changed dramatically over the last 15 years, with more effectively, and bone and cartilage destruction can largely be
effectiveinterventionsintroducedearliertopreventjointdamage prevented.Nevertheless, it is important torecognize that RA is a
and functional impairment. Current recommendations from the systemic disease and other disease manifestations may still be
EuropeanLeagueAgainstRheumatism(EULAR)andtheAmerican presenteventhoughjointdamagehasbeencontrolled. Although
in the past, the clinical understanding of disease burden empha-
sized destruction of the joints, now it must also focus on the
systemic manifestations associated with RA, including comorbid-
Supported by a grant from Novartis Pharma AG. The authors received no
ities, psychosocial aspects, and health-related quality of life
compensationfortheirinvolvementinthisproject.
The funding source did not have any involvement in the content, or in the (HRQOL)impairments(Fig.1).
collection,analysis,andinterpretationofpublisheddata,includedinthismanu-
script. BioScience Communications, New York, NY, provided assistance in the
writingof the manuscript with directguidance bythe authors. The decisionto Methods
submit the manuscript for publication was made by the authors without any
influencefromthefundingsource.
nCorrespondingauthor. Toidentifythe extra-articularburdenof RA,weinitiallylisted
E-mailaddress:[email protected](M.Cutolo). systemic complications and psychosocial factors associated with
0049-0172/$-seefrontmatter&2014ElsevierInc.Allrightsreserved.
http://dx.doi.org/10.1016/j.semarthrit.2013.08.004
480 M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488
Fig.1. SchematicofRAdiseaseburden.
the disease based on our clinical experience and then conducted traditional risk factors, including dyslipidemia, hypertension, and
literature searches on MEDLINE to identify relevant articles pub- diabetes,mayalsobemorecommoninRA,buttheevidenceisless
lished in English from January 2003 to December 2012. Search clear [10–13]. Nevertheless, the higher prevalence and clustering
termsincluded“rheumatoidarthritis”incombinationwith“cardio- oftraditionalriskfactorsdonotappearsufficienttoexplainallthe
vascular,”“osteoporosis,”“lung,”“pulmonary,”“infection,”“cancer,” excess cardiovascular risk [14,15]. The additional cardiovascular
“malignancy,” “fatigue,”“depression,”“cognition,” “cognitivedys- risk in RA likely depends on high-grade systemic inflammation
function,”“qualityoflife,”“workperformance,”or“disability.”Pre- interactingwithtraditionalaswellasnontraditionalriskfactors.
ference was given to articles describing clinical studies with The excess cardiovascular risk is present in early RA and
randomizedcohortsandlarge(4100)samplesizes.Of378refer- increases with longer disease duration [16]. Studies have found
encesidentifiedbytheinitialsearch,118providedrelevantclinical evidence of endothelial dysfunction as measured by impaired
orepidemiologicdataandwereselectedforinclusion.References brachialarteryvasodilation[17]andsubclinicalatherosclerosisas
identifiedbyMEDLINEweresupplementedbyreviewingreference measuredbyincreasedcarotidarteryintima–mediathicknessand
lists in selected articles and by abstracts presented at recent carotidplaquewithinthefirstyearfollowingRAdiagnosis[17,18].
rheumatologymeetings. Although vascular function and morphology may be impaired in
RAcomparedwiththegeneralpopulation,manystudieshavebeen
unable to find associations between systemic inflammation and
Results thesevascularchanges[19].RApatientswhoareasymptomaticfor
cardiovasculardiseasealsohaveincreasedratesofpericardialand
Systemiccomorbidities cardiacvalvularinvolvement[20,21].
EpidemiologicaldatasuggestthatRAconfersariskofmyocar-
Cardiovasculardisease dialinfarctionsimilartothatwithdiabetes[22],andobservational
RApatientshaveanapproximately2-foldhighercardiovascular studies show similar subclinical atherosclerotic activity in the 2
risk compared with the general population [6]. Some traditional disorders[23,24].Accordingly,RAmaybeconsideredasacoronary
cardiovascularriskfactorsaremorecommoninRAcohortsthanin heart disease risk-equivalent disorder [25]. Importantly, cardio-
controls, including insulin resistance [7], altered fat distribution vascularriskpredictiontoolsdevelopedinthegeneralpopulation,
[8], cigarette smoking [7], and physical inactivity [9]. Other such as the Framingham Risk Score, may underestimate the
M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488 481
cardiovascular risk in RA patents [26]. These prediction tools do acytokinethatisessentialforthedifferentiationandactivationof
not take nontraditional risk factors into consideration, including osteoclastsleadingtoboneresorption[48].Inflammationpresentin
RAdiseaseactivity,rheumatoidfactorpositivity,radiographicjoint synovial jointsmayalso inhibitWnt signaling, leading to reduced
damage, and glucocorticoid use, all of which may contribute to osteoblast functionand inhibition of bone formation [48]. Consis-
cardiovascularrisk[27].Becauseofthislimitation,EULARrecom- tentwiththeroleofsystemicinflammationinosteoporosis,theuse
mends multiplying the Framingham Risk Score by 1.5 in RA ofTNF inhibitors was associatedwith reduced fracture riskin the
patients with disease duration 410 years, seropositivity, or CORRONAregistry[45].Moreover,severalcaseseries,aswellasan
extra-articular manifestations [6]. Taken together, these observa- analysis of the phase 3 Efficacy and Safety of Adalimumab and
tions underscore the importance of aggressive control of inflam- Methotrexate (MTX) Versus MTX Monotherapy in Subjects With
mation and management of dyslipidemia and other traditional Early Rheumatoid Arthritis (PREMIER) study, suggest that TNF
cardiovascularriskfactorsinRApatients. inhibitorsmayslowbonelossinRA[49,50].
Substantialevidenceexiststosupportacardioprotectiveeffect Giventheriskofosteoporosisanditspotentialadverseimpacton
ofmethotrexateinpatientswithRA.Treatmentwithmethotrexate outcomes,itisimportantforat-riskRApatientstoundergoregular
is associated with reduction in the risks for acute myocardial monitoring of bone mineral density and to receive calcium and
infarction [28], congestive heart failure[29], and stroke [28]. The vitamin D supplementation and preventive therapy as needed. Of
reduction in cardiovascular events translates into a decreased note,vitaminDdeficiencywasrecentlylinkedtoincreasedriskand
likelihood of mortality. A prospective cohort study of 1240 RA severityofRA[51].ScreeningandmanagementofosteoporosisinRA
patientsfounda70%reductionintheriskofcardiovasculardeath patientshaveimproved,althoughprogressisstillneeded[52–54].
withtheuseofmethotrexatecomparedtothenon-useofDMARDs
[30].Fewdataexisttoelucidatethepotentialmechanismsunder-
Respiratorydisease
lying these benefits. It has been hypothesized that the systemic
Interstitial lung abnormalities are commonly observed in RA,
anti-inflammatoryeffectsofmethotrexate,includingdownregula-
even in patients with early disease who have no respiratory
tionofproinflammatorycytokinesknowntoplayaroleinathero-
symptoms. On high-resolution computed tomography (HRCT) of
genesis,mayexplainthereducedrisk[31].
126RApatients,themostfrequentlyobservedabnormalitieswere
Clinicaltrialshaveshownthebenefitsoftumornecrosisfactor
bronchialdilatation(41%),ground-glassattenuation(27%),paren-
(TNF) inhibitors and other biologics in slowing or preventing
chymalmicronodules(15%),subpleuralmicronodules(15%),retic-
progressive joint damage, but these trials were not sufficiently
ulation(12%),andbronchialwallthickening(12%)[55].Measures
poweredtodetectchangesincomorbidcardiovascularrisk[32,33].
ofsmallairwaydisease,includingparenchymalmicronodulesand
A number of observational registries and meta-analyses indicate
bronchialwallthickening,weremoreprominentinpatientswith
that TNF inhibitor therapy may reduce cardiovascular risk, with
long-standing RA than with early RA, whereas there was no
resulting decreases in major cardiovascular events, myocardial
differencebetweenthesesubgroupsinthefrequencyofinterstitial
infarction, and stroke [32–34]. Other studies suggest that the
abnormalitiessuchasground-glassattenuationandreticulation.
cardiovascularriskreductionwithTNFinhibitorsmaybeconfined
Thelifetimeriskofdevelopinginterstitiallungdisease(ILD)is
to patients who respond to these agents [35] and may not differ
substantially higher in RA patients than in those without RA, as
substantiallyfromthebenefitseenwithprolongeduseofconven-
illustrated by a recent population-based study [56]. An inception
tional DMARDs[28,36]. The exact mechanisms by which biologic
cohortof 582 RA patients was followed for a mean of 16.4 years
and conventional DMARDs as well as glucocorticoids may affect
and compared with a matched cohort of 603 controls. The
cardiovascular risk are multiple and remain largely unresolved.
cumulative 30-year risk of ILD in these respective groups was
Beneficial effects of anti-TNF therapy on blood pressure control
7.7%and0.9%,whichtranslatedintoahazardratioof8.96(95%CI,
[37], possiblyby reducing systemic vascular resistance [38], have
4.02–19.94).TheriskofdevelopingILDwasassociatedwitholder
been described, whereas the opposite has been shown for long-
age at time of RA onset, male gender, and greater RA disease
term glucocorticoid therapy [39]. Effects of anti-TNF therapy and
severity. Moreover, RA patients who developed ILD had a 3-fold
glucocorticoidtherapyonlipidandinsulinmetabolism,aswellas
increaseinmortalitycomparedwithRApatientswithoutILD.
onbodycomposition,appearfarmorecomplex[7,10,11,40–43],as
The cause of ILD in RA is unknown, although DMARDs, TNF
aretheeffectsonvascularfunctionandmorphology[19].
inhibitors, and glucocorticoids have been associated with it [57–
60].DespitetheapparentabsenceofpulmonarytoxicitywithTNF
Osteoporosis
blockers in large randomized clinical trials, new-onset ILD or
RAisassociatedwithsystemicbonelossandincreasedfracture
exacerbation of preexisting ILD with high mortality has been
risk,likelyreflectingcontributionsfrommultiplefactors,including
reported in 144 RA patients following the use of TNF blockers
disease activity, physical inactivity, and glucocorticoid use. In the
[61].MarkedfollicularB-cellhyperplasiahasbeendetectedinRA-
BritishGeneralPracticeDatabaseof 430,000RApatients,therisk
associated interstitial pneumonia [62]. This suggests that ritux-
ofhipfracturewasincreasedby2.0-foldandvertebralfractureby
imab, which targets CD20 to deplete B cells, may be useful in
2.4-foldrelativetonon-RAcontrols[44].IntheRAcohort,disease
treatingbothRAandassociatedILD[63].However,rituximabhas
duration 410 years, low body mass index, and use of oral
alsobeenassociatedwithnew-onsetILDinisolatedpatientswith
glucocorticoids were independently associated with increased
RA [61]. Other morphological assessments show that mast cells
hipfracturerisk.IntheConsortiumofRheumatologyResearchers and CD4þ cells are also prominent in RA-associated interstitial
ofNorthAmerica(CORRONA)registry,whichincluded8419female
pneumonitis lesions [64,65]. Both cell types are important in the
RA patients, postmenopausal status, higher modified Health
rheumatoidsynovium,andthereforeitmayalsobetherapeutically
Assessment Questionnaire (mHAQ) score, and glucocorticoid use
feasible to target these cells or their products against both joint
wereassociatedwithhigheroverallfracturerisk[45].
andlungdiseasesinRA.
Systemicinflammation,measuredbyhigh-sensitivityC-reactive
protein (hs-CRP) levels, has been associated with fracture risk in
healthycohorts[46,47].Mechanistically,proinflammatorycytokines Infection
producedbytherheumatoidsynovium,includingTNF,interleukin RA is associated with increased infection risk, which may be
(IL)-1, IL-6, and IL-17, can directly or indirectly upregulate the attributedtoeitherimpairedimmunefunctionassociatedwiththe
expression of the receptor activator of nuclear factor-κB (RANKL), disease itself or an effect of immunosuppressive therapy. In the
482 M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488
population-basedRochesterEpidemiologyProject,objectivelycon- intheNationalDataBankofRheumaticDiseases,theuseofinflixi-
firmed infections and infections requiring hospitalization were mab or etanercept increased the odds of melanoma by approx-
morecommonamongRApatientscomparedtothosewithoutRA; imately 2.5-fold, and infliximab also increased the odds of non-
the adjusted hazard ratios were 1.70(95% CI,1.42–2.03) and1.83 melanoma skin cancer by 1.7-fold [85]. A recent report from the
(95%CI,1.52–2.21),respectively[66].Infectionriskassociatedwith BSRBR registry showed that TNF inhibitors (SIR ¼ 1.72) and
RA was most evident in bone, joints, skin, soft tissues, and the conventionalDMARDs(SIR ¼ 1.83)increasedtheriskofbasalcell
respiratory tract. In this study, increasing age, the presence of carcinomaandsquamouscellcarcinomainRAcomparedwiththe
extra-articular RA manifestations, leukopenia, comorbidities, and general population [86]. Taken together, these findings suggest
theuseofglucocorticoidswerepredictiveofinfectionrisk[67].RA that treated RA patients should use sunprotection and be moni-
was also independently associated with an increased risk of toredforskincancer.
pneumoniainalargepopulation-basedcase–controlstudyinvolv- Pooled analyses of clinical trials found that rituximab, abata-
ing 417,000incidentcases;theoddsratiowas1.84(95%CI,1.62– cept, and tocilizumab were not associated with malignancy risk
2.10)afteradjustingforotherpneumoniariskfactors[68].Serious [87–89], but further evaluation in real-world clinical practice is
infectionwas reported at a rate of 46.4 events per 1000 patient- stillneeded.
years in a retrospective cohort of RA patients aged Z66 years,
which was higherthantherateseeninyounger RAcohorts[69].
Psychosocialaspects
Factors predictive of infection risk in the elderly included higher
comorbidity,ruralresidence,greaterdiseaseseverity,and history
Health-RelatedQualityofLife(HRQOL)
ofpreviousinfection,withtheriskfurtherincreasedbyglucocor-
HRQOL is significantly impaired in RA owing to pain, fatigue,
ticoid useandtoalesserextentbytheuseofTNFinhibitorsand
and functional deficits [90]. Moreover, the decrements in HRQOL
DMARDs.
are associated with reduced productivity, work loss, and work
In a retrospective cohort of 27,710 RA patients, the use of
disability.TheShortForm-36(SF-36)isthetoolmostoftenusedto
DMARDs (without glucocorticoids) did not influence the risk of
assessHRQOLinRA.Itconsistsof36questionsacross8domains,
serious infection, whereas the use of glucocorticoids was associ-
includinglimitationsinphysicalfunction,rolephysical,bodilypain,
ated with an increased serious infection risk (adjusted rate ratio
general health, vitality, social functioning, role emotional, and
for glucocorticoids vs no use of DMARDs or glucocorticoids: 1.9
mental health. The domains are summarized to yield physical
[95% CI, 1.75–2.05]) [70]. Subsequent findings from a healthcare
component summary (PCS) and mental component summary
database analysis supported the increased risk associated with
(MCS)scores,whichrangefrom0(worst)to100(best)andwhich
glucocorticoid therapy: among RA patients aged Z65 years,
arecomparedtoage-andsex-matchednormshavingameanof50.
treatment with prednisolone 5mg/day or equivalent for 3 years
The impact of RA on HRQOL is evident from a study of SF-36
was associated with a 2-fold risk of current serious infection vs
datacollectedfrompatientswithRAandhealthycontrols(Fig.2)
non-use(adjustedoddsratio2.00[95%CI,1.69–2.26])[71].Meta-
[91]. The findings are consistent with SF-36 data collected at
analyses of controlled clinical trials indicate that TNF inhibitors
baselineinlargerandomized,controlledtrialsofvariousbiologics,
showanon-significanttendencytoraiseseriousinfectionrisk[72–
in which the greatest impairments were seen in the physical
74]. In the prospective CORRONA registry involving 7971 RA
function,rolephysical,bodilypain,andvitalitydomainsandthus
patients, the adjusted rate of infection was higher with metho-
were reflected more in the PCS than in the MCS measure. In the
trexate compared with other conventional DMARDs and was
Etanercept in Early RA (ERA), Combination of Methotrexate and
further increased by the use of TNF inhibitors either alone or in
EtanerceptinActiveEarlyRA(COMET),andPREMIERtrials,where
combinationwithmethotrexate[75].TNFinhibitorsusedaloneor
patients had RA for a mean duration o1 year, the baseline PCS
in combination with methotrexate also increased opportunistic
scores were 28–32 and the baseline MCS scores were 42–47
infections. In the British Society for Rheumatology Biologics
[92,93]. In general, similar decrements were seen in trials of
Register(BSRBR),TNFinhibitorswereassociatedwithanincreased
patientswithestablishedRA[94–96].
risk of serious infection compared with conventional DMARDs,
Theeffectoftreatmentisgreatestinmagnitudeonthedomains
particularly during the first 6 months of therapy [76]. Finally,
having the lowest scores at baseline, and consequently improve-
recent data from the Dutch Rheumatoid Arthritis Monitoring
ments in PCS are greater than those in MCS [90]. In early-stage
(DREAM) registry suggests that the risk of serious infection with
disease,theimprovementinHRQOLwithmethotrexateissimilar
TNFinhibitorsvariesbyagent,withetanercepthavingalowerrisk
in magnitude to the improvement with TNF inhibitors [92]. In
than the anti-TNF monoclonal antibodiesadalimumab and inflix-
patients on background methotrexate therapy, the addition of a
imab[77].
TNF inhibitor or another biologic produces significantly greater
HRQOL improvement compared with adding placebo [93–97].
Malignancy
Nevertheless,thePCS,MCS,anddomainscoresremainbelowthe
RA may confer an increased risk of certain malignancies but
normative mean of 50, indicating that HRQOL is still impaired
mayprotectagainstothers.Inameta-analysis,RAwasassociated
compared to age- and sex-matched healthy controls. Moderate
witha2-foldincreaseintheriskoflymphomacomparedwiththe
improvements in HRQOL with TNF inhibitor therapy have also
generalpopulation(standardizedincidenceratio[SIR]¼2.08;95%
beendetectedusingotherinstruments,includingtheEuroQol-5D
CI, 1.80–2.39), with higher risk for Hodgkin lymphoma (SIR ¼
andtheShortForm6D[98].
3.29)thanfornon-Hodgkinlymphoma(SIR ¼ 1.95)[78].RAwas
alsoassociatedwitha63%increasedriskoflungcancercompared
with the general population but with a 23% decreased risk of Fatigue
colorectal cancer and a 16% decreased risk of breast cancer. TNF Fatigueisasubjectivefeelingofdebilitatingtirednessorweak-
inhibitors, whether used alone or with methotrexate, were not nessthatinterfereswithphysicalandsocialactivities.InRA,fatigue
associated with lymphoma risk in large observational registries differsfromnormaltirednessinthatitisextreme,oftenunrelated
[79,80], although some association between TNF inhibitors and to prior activities, and unresolving [99]. Fatigue is significantly
lymphomariskhasbeenreportedinsmallcohorts[81,82]. more pronounced in RA patients compared with healthy controls
SeveralreportssuggestthatTNFinhibitorsincreasetheriskof [100,101]. In a study comparing 122 RA patients with the same
melanoma and non-melanomaskin cancer [83–85]. Forexample, number of matched controls, greater fatigue was associated with
M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488 483
Healthy Controls Rheumatoid Arthri(cid:2)s
90
83
79
80 73 72 72
e
or 70 64
c 60
n s 60 57
36 domai 4500 42 30 30 44 50 38 47 42 5032 4639
F- 30
S
an 20
e
M 10
0
PF RP BP GH MH RE SF VT PCS MCS
SF-36 domains
Fig.2. ShortForm-36healthdomainscoresinrheumatoidarthritispatientsandhealthycontrols.PF,physicalfunctioning;RP,rolephysical;BP,bodilypain;GH,general
health;MH,mentalhealth;RE,roleemotional;SF,socialfunctioning;VT,vitality;PCS,physicalcomponentsummaryscore;MCS,mentalcomponentsummaryscore(91).
more anxiety, disability, and social stress, and less social support depressivesymptomsareincluded,theprevalencemaybeashigh
[101]. In a 1-year longitudinal study, the proportions showing as40%[115].Depressionhasnotbeenconsistentlycorrelatedwith
increasedvsdecreasedfatigueseverityweregenerallycomparable disease activity or progression in RA [107,109]. However, depres-
(54%and45%,respectively)[102].Surprisingly,baselineinflamma- sionhasanadverseimpactonoutcomes;ithasbeenfoundtobe
tionreflectedbytheerythrocytesedimentationratewasnegatively associated with increases in mortality [116], cardiovascular mor-
relatedto fatigue1 yearlater. Inaddition,perceptionsatbaseline bidity [117] including myocardial infarction [118], and disability
that RA has severe consequences and is uncontrollable predicted [119].Moreover,depressionisassociatedwithreducedHRQOL.Ina
greaterfatigueat1year.Giventhewell-establishedassociationof cohort of 307 RA patients who were followed up for 2 years,
anemiawith inflammation, potential correlations of fatigue in RA depressive symptoms were more important than radiographic
withdecreasedhemoglobinlevelshavebeeninvestigated[103,104]. damage or disease activity as predictors of decrements in the
Findings have been negative, however, and swollen and tender MCSoftheSF-36[120].
joint count, pain, and patient function were shown to be more TheetiologyofdepressioninRAisnotclear.However,patients
importantcorrelatesoffatigueintheRApopulation. arecharacterizedashavingahighprevalenceofmajorlifeevents
Severalinstrumentshavebeenused to assessfatiguein RAand preceding the onset of RA and the presence of personality
other conditions, including the Profile of Fatigue (ProF) and the disorders[121].Inaddition,themultiplelevelsofstressresponse
Multidimensional Fatigue Inventory (MFI) [105]. In clinical studies, system activation in RA may ultimately influence disease-related
fatigue is more often assessed with the Functional Assessment of outcomes such as depression [122]. Depressive symptoms have
ChronicIllnessTherapy-Fatigue(FACIT-Fatigue)scale,whichhasbeen beenassociatedwithsystemicinflammation,measuredbyhs-CRP
validated for use in RA [106]. FACIT-Fatigue is strongly associated levels,inmultipleRAcohorts[123–125].Forexample,inacohort
withthevitalitydomainontheSF-36andhastheabilitytodistin- of 218 RA patients, depression scores measured using the Beck
guishpatientsaccordingtoACRresponselevels.FACIT-Fatigueisalso DepressionInventoryIIwerepositivelycorrelatedwithCRPlevels
correlatedwithHealthAssessmentQuestionnaire(HAQ)andpatient (r ¼ 0.46;P o 0.001),andbothweresignificantlycorrelatedwith
globalandpainvisualanalogscores[107].FACIT-Fatigueconsistsof pain [125]. Proinflammatory cytokines have been postulated to
13questionsscoredona0-4Likertscale;totalscoresrangefrom0to playarolein depressionbyaltering thehypothalamic–pituitary–
52,withhigherscoresindicatingmorefatigue. adrenal axis, but this remains an unproven hypothesis [126,127].
Theimpactofbiologicsonfatiguehasbeenevaluatedinclinical Amongcytokines,IL-6hasbeenthemostconsistentlyelevatedin
studies. In the adalimumab trials, the improvement in FACIT- depression, but little evidence is available to link this cytokine
Fatiguerangedfrom (cid:2)3to (cid:2)7pointsacrosstrials,withachange withdepressioninRA[128].
of–4pointsconsideredtorepresentaminimumclinicallyimpor-
tantdifference[108].However,ameta-analysisof10randomized
Cognitivedysfunction
trials concluded that the effectof biologics on fatigue was small:
Cognitiveimpairmentwasreportedin30%ofRApatientsina
theeffectsizewas0.45(95%CI,0.31–0.58)forbiologicsoveralland cross-sectionalstudy,withRApatientshavingsignificantlypoorer
0.36(95%CI,0.21–0.51)forTNFinhibitors[109].Themechanismof scores for verbal fluency, logic memory, and short memory
fatigueinRAremainstobedetermined[110].Itdoesnotcorrelate
compared with healthy controls [129]. In this study, cognitive
with erythrocyte sedimentation rate or joint counts, suggesting
impairmentwasunrelatedtoRAclinicalortreatmentfeaturesor
thatitisnotsimplyamanifestationofinflammatoryjointdisease.
to disability. In another longitudinal cohort study, RA patients
Elevated circulating cytokine levels may contribute to fatigue, wereclassifiedascognitivelyimpairediftheyperformed1stand-
inasmuch as TNF inhibitors and other biologics produce some
ard deviationbelowage-basedpopulation normsonat least4 of
improvementinfatigue.However,otherfactorsincludingcomor-
16 indices derived from 12 standardized neuropsychological
biddepressionandanxiety,andlackofsocialsupport,mayalsobe measures [130]. Overall, 31% of the patients met this definition
importantcontributorstofatigue[111,112].
of cognitive impairment. Aftergender, race, disease duration and
severity,hs-CRPlevel,anddepressionwerecontrolledfor,4factors
Depression independently predicted increased cognitive impairment: low
Depressionis commoninRAand isestimated tooccurin13– education, low income, use of oral glucocorticoids, and the
20% of patients [113]. Forexample, in the baseline assessmentof presence of cardiovascular risk factors. The same investigators
comorbidityintheBSRBRregistry,19%ofpatientshadpreviously also showed that the objective assessment based on the 12
received a formal diagnosis of depression [114]. When mild standardized neuropsychological measures was not significantly
484 M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488
correlated with the cognitive impairment perceived by patients, toworkhadbetterclinicalstatusmeasuresandself-reportscores
althoughpatient-perceivedcognitiveimpairmentwassignificantly comparedtothosewhostoppedworking.Interestingly,theuseof
associated with both depression and fatigue [131]. Cognitive biologics was more common among those who stopped working
impairment was also associated with depression and pain [132], comparedwiththosewhocontinuedworking(39%vs32%inhigh
andwithbiocorrelatesofinflammationanddemyelinationinother grossdomesticproduct[GDP]countriesand13%vs8%inlowGDP
RAcohorts[133]. countries).Thesevaluescouldreflectselectionbiasinthatpatients
Interestingly, a long-term population-based study found that withmoreseveredisease,andhencegreaterworkdisability,may
RA in midlife was associated with a 2.77-fold higher risk of havebeenmorelikelytoreceivebiologictherapy.
cognitive impairment measured 2 decades later [134]. Moreover,
RAincreasedtheriskforsubsequentdevelopmentofAlzheimer's
diseaseby2.5-fold[134].InasmallcohortofelderlyRApatients, Discussion
TNFinhibitorssignificantlyimprovedMini-MentalStateExamina-
tionscoresfromameanof24.5atbaselineto26.3after6months The RA disease burden extends beyond the joint to include
[135]. However, further work is needed to determine how treat- other tissues and organs, involving multiple comorbidities and
ment influences cognitive dysfunction in the general RA psychosocial manifestations. With the introduction of DMARDs
population. andbiologics,considerableprogresshasbeenmadeinaddressing
theburdenassociatedwithjointdamage,andnowthefocusneeds
Workperformanceanddisability to shift to reducing other aspects of the disease burden. Toward
RA causes work limitations across all domains of the Work thisobjective,promisingstrategiesincludepersonalizedmedicine,
LimitationsQuestionnaire,correspondingtoa5%decreaseinwork whichfocusesonmanagingriskfactorsandidentifyingpredictive
productivity [136]. However, RA patients tend to select jobs that biomarkers, and research on emerging treatments that target
theycanperformwithintheirlimitations;consequently,measures recently identified mechanisms in the complex pathophysiology
ofworklimitationarenotaffectedtothesameextentbyRAasare ofRAanditsrelatedsystemicexpressions.
HAQ and HRQOL measures [136]. Besides the limitation in pro- Personalized medicine recognizes that the disease course and
ductivity, RA causes an estimated 30–40% of patients to stop burden differ across individual patients. Risk factors need to be
working[137–139].HAQisthemajorpredictorofworkdisability, considered to identify which RA patients are at increased risk of
with patients who have manual jobs most likely to discontinue specific disease manifestations, and similarly, predictive bio-
working[140]. markers are needed toidentify which treatments areoptimal for
Work disability has been related to treatment response, with a given patient. Risk factors for many RA comorbidities are well
the highest rates for nonresponders, intermediate rates for ACR recognized. For example, hypertension, dyslipidemia, insulin
20% improvement criteria (ACR20) or ACR 50% improvement resistance, diabetes, obesity, lackof exercise, and cigarettesmok-
criteria (ACR50) responders, and the lowest rates for those ingarewell-knowncardiovascularriskfactors.Therefore,aggres-
achieving remission with DMARD therapy [141]. Similarly, work siveriskfactormanagementmaybenecessaryineachRApatient
productivity has been improved in clinical studies of TNF inhib- in order to reduce comorbid cardiovascular risk, consistent with
itors,ofteninassociationwithimprovementsinPCSontheSF-36 the approach taken in patients with established cardiovascular
[142–144].Nevertheless,workdisabilityremainsamajorproblem disease.
inRA,eveninearly-stagedisease[145]. With multiple therapeutic options available, predictive bio-
In the Quantitative Standard Monitoring of Patients with RA markersareneededtohelpguidetreatmentdecisionsforindivid-
(QUEST-RA) database, which included information on 8039 ual patients. Additionally, earlier diagnosis would enable
patientsfrom32countries,37%ofRApatientswhowereworking healthcare providers to initiate therapeutic interventions more
at the time of diagnosis reported work disability at some point quickly,whentreatmentismostlikelytopreventprogressivejoint
becauseofthedisease[140].Forpatientsdiagnosedinthe2000s, damageandreducethesystemicinflammationthatcontributesto
theprobabilityofcontinuingtoworkwas80%at2yearsand68% variousextra-articularandpsychosocialmanifestations.
at 5 years, with similar patterns in countries with high and low TheintroductionofDMARDsenabledanapproachtotreatment
grossdomesticproduct(Fig.3).Ingeneral,patientswhocontinued based on the control of inflammatory reactions and immune cell
Men Women
100 100
90 90
80 80
% %
k, 70 k, 70
r r
wo 60 wo 60
o o
y t 50 y t 50
bilit 40 bilit 40
a a
ob 30 Countries with GDP <11K USD ob 30 Countries with GDP <11K USD
Pr 20 Countries with GDP >24K USD Pr 20 Countries with GDP >24K USD
10 10
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time, years Time, years
Fig.3. Probabilityofmen(leftpanel)andwomen(rightpanel)continuingtoworkfollowingadiagnosisofrheumatoidarthritisinthe2000sincountrieswithhighorlow
grossdomesticproduct(GDP).DatafromtheQUEST-RAstudy(140).(ReprintedwithpermissionfromBioMedCentral:ArthritisResearch&Therapy12:R42,copyright2010.)
M.Cutoloetal./SeminarsinArthritisandRheumatism43(2014)479–488 485
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