Rev. Bras. Reumatol. vol.57 número6

w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

Socioeconomic

and

therapy

factor

influence

on

self-reported

fatigue,

anxiety

and

depression

in

rheumatoid

arthritis

patients

Mirjana

Lapˇcevi´c

_,

_Mira

_Vukovi´c

_,

_Branislav

_S.

_{Gvozdenovi´c}

,

Vesna

Mioljevi´c

,

Sne ˇzana

Marjanovi´c

a_{PrimaryHealthcareCenter,DepartmentofGeneralMedicine,Belgrade,Serbia} b_{GeneralHospitalValjevo,EducationCenter,Belgrade,Serbia}

c_{PharmaceuticalProductDevelopmentSerbia,PharmacovigilanceDepartment,Belgrade,Serbia} d_{ClinicalCenterofSerbia,DepartmentofHospitalEpidemiologyandNutritionHygiene,Belgrade,Serbia} e_{GeneralHospitalValjevo,DepartmentofPsychiatry,Valjevo,Serbia}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received22March2016 Accepted20December2016 Availableonline11March2017

Keywords:

Rheumatoidarthritis TherapyFatigue Anxiety Depression

a

b

s

t

r

a

c

t

Introduction:Fatigue,anxietyanddepressionareveryfrequentsymptomsinpatientswith rheumatoidarthritis(RA).

Goals:Inthisstudyweevaluatedtheinfluenceofsocioeconomiccharacteristics,therapyand comorbiditiesontheself-reportedhighfatigue,anxietyanddepressioninpatientswithRA. Method:Multicenter cross-sectional study was performed in 22 health institutions in SerbiaduringtheperiodfromApril–August2014inpopulationofolderRApatients. Self-reportedpatientshealthstatuswasmeasuredby:FatigueAssessmentScale,PatientHealth Questionnaire-9andGeneralizedAnxietyDisorder-7.Treatmentmodalitiesweredefined as: (1) non-steroidal anti-inflammatory drugs (NSAIDs)and/or analgesics and/or corti-costeroids; (2) synthetic disease-modifying antirheumatic drugs (DMARDs)alone or in combinationwithcorticosteroidsand/orNSAIDsand(3)anyRAtreatmentwhichincludes biologicDMARDs.

Results:Thereweresignificantpredictorsofhighdepression:syntheticDMARDstherapyin combinationwithcorticosteroidsand/orNSAIDs,physiotherapistself-payment,frequent taxiuse,alternativetreatmentandemploymentstatus.Theneedforanotherperson’s assis-tance,supplementalcalciumtherapyandprofessionalqualificationswerethepredictorsof ahighfatigue,whereastheageabove65yearshadtheprotectiveeffectonit.Anxietywasan independenthighfatiguepredictor.Thepredictorsofahighanxietywere:gastroprotection withproton-pumpinhibitorsandpatientoccupation.

∗ _{Correspondingauthor.}

E-mail:[email protected](B.S.Gvozdenovi´c).

http://dx.doi.org/10.1016/j.rbre.2017.02.004

Conclusion: Socioeconomicpredictorsofself-reportedhighdepression,anxietyorfatigue aredifferentforeachofthementionedoutcomes,whileaccompaniedwiththebasicRA treatmenttheyexclusivelyexplainahighdepression.Theanxiety,jointedwiththe socioeco-nomicvariablesandsupplementaltherapy,isasignificantfatiguepredictorinRApatients. ©2017ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Influência

de

fatores

socioeconômicos

e

de

tratamento

sobre

a

fadiga,

ansiedade

e

depressão

autorrelatadas

em

pacientes

com

artrite

reumatoide

Palavras-chave: Artritereumatoide TratamentoFadiga Ansiedade Depressão

r

e

s

u

m

o

Introduc¸ão:Afadiga,aansiedadeeadepressãosãosintomasmuitofrequentesempacientes comartritereumatoide(AR).

Objetivos: Neste estudo, avaliou-se a influência de características socioeconômicas, característicasdetratamentoecomorbidadesnaelevac¸ãonafadiga,ansiedadeedepressão autorrelatadasempacientescomAR.

Método: Esteestudotransversal multicêntricofoi feitoem 22instituic¸ões desaúdena Sérviadeabrilaagostode2014napopulac¸ãodepacientesidososcomAR.Ostatusde saúdeautorrelatadodospacientesfoimedidopelosinstrumentosFatigueAssessmentScale, PatientHealthQuestionnaire-9eGeneralizedAnxietyDisorder-7.Asmodalidadesdetratamento foramdefinidascomo:1)anti-inflamatóriosnãoesteroides(AINE) e/ouanalgésicose/ou corticosteroides;2)fármacosantirreumáticosmodificadoresdadoenc¸asintéticos(DMARD) isoladamenteouemcombinac¸ãocomcorticosteroidese/ouAINEe3)qualquertratamento paraaARqueincluísseDMARDbiológicos.

Resultados: Houvepreditoressignificativosdedepressãoelevada:tratamentocomDMARD sintéticos em combinac¸ão com corticosteroides e/ou AINE, pagamento particular de fisioterapia,usofrequentedeservic¸osdetáxi,terapiasalternativasestatusocupacional. Anecessidadedeassistênciadeoutrapessoa,otratamentosuplementarcomcálcioeas qualificac¸õesprofissionaisforamospreditoresdefadigaelevada.Aidadeacimade65anos teveumefeitoprotetorsobreafadigaelevada.Aansiedadefoiumpreditorindependente defadigaelevada.Ospreditoresansiedadeelevadaforam:gastroprotec¸ãocominibidores dabombadeprótonseocupac¸ãodopaciente.

Conclusão: Os preditoressocioeconômicos de níveiselevados de depressão, ansiedade ou fadiga autorrelatadas são diferentes para cada um dos desfechos mencionados; quandoacompanhadosdotratamentobásicoparaaAR,essespreditoressocioeconômicos explicam exclusivamente uma depressão elevada. A ansiedade, associadaàs variáveis socioeconômicaseaotratamentocomplementar,éumimportantepreditordafadigaem pacientescomAR.

©2017ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Rheumatoidarthritis(RA)isamultifactorialsystemicchronic inflammatorydisease that primarilycauses pain, swelling, joint stiffness and loss of joint function.1 _{If not properly}

treatedtheRAcancausejoint damageincluding their per-manentdestruction.2_{TheRAcausesjointdamageduringthe}

firstorsecondyearofthedisease.Thatiswhyanearly diagno-sisandanadequatetreatmentofRAareveryimportant.The RAtreatmentgoalistheachievementofclinicalremission, i.e.discontinuationofthediseaseactivity.3_{Byincludingone}

synthetic Disease-Modifying Antirheumatic Drug (DMARD) or, if necessary, two of them in combination during six monthsitisexpectedtoachievetheremissionoratleastthe lowRAactivity.If notachievedwithsyntheticDMARDsthe

biologicDMARDsshouldalsobeincluded.Besidesthe afore-mentioned therapy, non-steroidal anti-inflammatory drugs (NSAIDs)shouldbeincluded,togetherwithcorticosteroidsif needed, inorder tocontrolthe painand theinflammation andimproveRApatient’sgeneralhealthcondition.Duringthe administrationoftheabovementionedtherapy,itis neces-sarytoprotectthedigestivetractbleedingwithproton-pump inhibitors (PPI), especially in patients with high gastroin-testinalbleedingrisk.Inaddition,regularhematologicaland biochemicallaboratoryresultsfollowupsareneededinorder tomonitorapossiblemarrowbonedamageandhepatotoxicity duringtheDMARDsadministration.4,5

overwhelming,sustainedsenseofexhaustionanddecreased capacity for physicaland mental work”.6 _{The RApatients}

definetheirfatigueaspersistent,multidimensionalsymptom withsevere,longtermconsequencestotheirdailylife7–9 _or

asasymptomthatdisruptstheirdailyactivitiesandcauses anon-refreshingsleep.10_{Severalstudieshaveshownthatthe}

highfatigueinRApatientswasrelatedtothepain,depression symptoms, sleepdisorder, high physicaleffort,genderand psychosocialfactors.11,12_{Otherreportsfoundthatdepression}

isrelatedtothepain,fatigue,inabilitytoworkandlower ther-apycompliance.13,14_{Somestudiesreportahighincidenceofa}

commondepressionandanxietyappearanceinRApatients.15

However,thereisalackofreportsintheliteratureabout com-moninfluencesofthebasic,adjuvantandsupplementalRA therapyandsocioeconomicfactorstotheanxiety,depression andfatigueinRApatients.

Study

goals

Theprimarygoalofthestudywastoevaluatetheinfluence ofthebasicRAtherapy,theadjuvantandsupplemental ther-apy,thedemographicandsocioeconomiccharacteristics,the RAcomplicationsand comorbiditiestotheanxiety, depres-sionandfatigueinRApatients.Thesecondaryobjectivewas toevaluatetherelationshipbetweenthedepressionandthe fatigueandanxietyofRApatients.

Methodology

Studylocationandtimeperiod

The study was conducted during the time period from April–August2014andincludedtheRApatientsfrom20 Ser-bianprimaryhealthcareinstitutions,onetertiaryhealthcare institution–InstituteofRheumatology,ClinicalCentreof Ser-bia, Belgrade, Serbia, and also two specialized health spa institutions–NiˇskaBanja,Niˇs,SerbiaandJodnaBanja,Novi Sad,Serbia.

Studydesign

Amulticenterepidemiologiccross-sectionalstudyinthe pop-ulationofolderRApatientswasconducted.Thecrosssection wasmadeaccordingtotheobtainedself-reportedoutcome categoriesofhighfatigueabsence/presence,highdepression absence/presenceandhighanxietyabsence/presence.

Patientsandprocedures

Thepatientsofbothgenderssufferingfrom RAolder than 18yearswereincluded.Thecriterionforexcludingpatients fromthestudywasatleastonemissinganswerinthefatigue, depressionoranxietyquestionnaires.

During onevisit tothe doctor the patients filled inthe surveythatcontainedquestionsgroupedintothreesections. Firstsectioncontainedquestionsrelatedtodemographicand socioeconomiccharacteristicsofthepatients.Thesecondone referredtothedurationofthedisease,typeanddurationof

the current RA therapy, aswell as the RAtreatment com-plications. Inthethirdsection therewere threemeasuring instrumentsofself-reportedhealthconditionofthepatient: “Fatigue Assessment Scale” (FAS) with 10 items; “Patient Health Questionnaire” (PHQ-9) with9 items,and “General-izedAnxietyDisorder”(GAD-7)with7items.Patientsneeded approximately30mintofilloutallthequestionnaires.

Variablesinthestudy

Theresultingvariables inthe studywere PHQ-9score,FAS scoreandGAD-7score.ThevaluesofFASscore≥22were con-sideredasahighfatigue.16_{HighanxietywasdefinedasGAD-7}

score≥10,17,18_{whilethehighdepressionwasdefinedbythe}

valuesofPHQ-9score≥10.19_{TheGAD-7andPHQ-9surveys}

containthequestionswithprovidedanswersaboutthe pres-ence ofthe problem thatcaused dificultiestothe patients duringthe previoustwoweeks,and whichwere numbered byascendingLikertordinalscalefrom0to3(0–notatall;1 –fewdays;2–morethanahalfofthetimeand3–almost everyday).ThePHQ-9surveyisusedtoevaluatethelevelof depression,20,21_{whiletheGAD-7wasprimarlydevelopedto}

evaluatethegeneralizedanxietydisorder.17_{TheFAScontains}

ten questionsthatdescribethe presenceofpossible condi-tionswithfiveprovidedordinalanswermodalitiesfrom1to5 (1–never;2–sometimes;3–ordinarily;4–often;5–always). TheresultingFASscorerangesfrom10to50.TheFASsurvey wasprimarlydesignedasaninstrumenttoevaluateand mon-itorthefatigueinthegeneralpatientpopulation,22_andithas

alsobeenvalidatedasareliablemasuringfatigueinstrument inthesarcoidosispatients.23

Theexamineddemographicandsocioeconomicvariables were: age, gender, marriage status, professional qualifica-tions,employmentstatus,occupation,theneedforanother person’s assistance, the need for frequent taxi use, phys-ioterapist payment, assisitance device use due to RA, the presenceofotherdiseases,osteoporosispresence,orthopedic surgicalinterventionandfracturedlimbscausedbytheRA. Theincludedtreatmentpredictorswere:currentRAtherapy status, current RAtherapy duration (months), periodfrom the beginning of the first RA symptoms until the start of the current therapy (months), proton-pump inhibitor and H2receptorantagonist useinordertoprotectthestomach, the use of supplements that contain glucosamine sulfat, chondroitin sulfat, hyaluronic acid, antirheumatic cream use, vitaminD3 and calcium consummation, self-initiative therapy cessation, stomach or duodenum bleeding during RA therapy, surgery performed because of the stomach or duodenum bleeding,aswell astheuse ofalternativeways of treatments. Thecurrent RAtherapy is defined bythree modalitiessuchas:(1)NSAIDsand/oranalgesicsand/or cor-ticosteroids;(2) syntheticDMARDsaloneor combinedwith corticosteroidsand/orNSAIDand(3)anyRAtreatmentwhich includes biologic DMARDs. There were also data recorded about the duration of the RA (months) as well as disease symptomsduration(months).

Statisticaldataprocessing

normaldistributionwasperformed.Inthedatawitha nor-maldistribution,thecontinous variablesaredescribedbya mean and a standard deviation, while the data that devi-atefromnormaldistribiutionaredescribedbyamedianand aninterquartile range. Thenominal variables are descibed by frequencyand percentage according to the appropriate categories.Inthe methodsofinferentialstatistics,the cor-relationof individual category predictors with each ofthe monitoredself-reportedoutcomes (absence/presenceofthe highfatigue,anxietyordepressionlevel)wasevaluatedbyPhi orCarmer’sVcorrelationcoefficient.Differenceevaluationin thecontinousnumericalvariablesbetweenthegroupwiththe presenceandthegroupwiththeabsenceofthetested self-reportedoutcomes,wasdonebyMann–Whitneymethod.The riskfactoranalysisforeachoftheself-reportedoutcomeswas donebythebinarylogisticregressionmethod.Theassessment oftherelationshipbetweenthelevelofdepressionwiththe fatigueandanxietylevelswasperformedbythemultiple lin-earregression(stepwisemethod).Thediagnosisofcollinearity betweenthe predictors inthe linear regression modelwas donebythearbitraryassesmentoftheconditionalindexand thevarianceinflationfactor(VIF).24,25_{Theabsenceofadoubt}

intheexistanceofthecollinearitywasdefinedbyaconditional indexlessthan15 andVIFvaluelessthan 3.Theaccepted levelofsignificancewas0.05.Thestatisticalanalysiswas con-ductedusingIBMSPSSStatistics20.Thisstudywasapproved bytheinstitution’s institutionalreviewboardand obtained patients’consent.

Results

Outof494patients,409ofthemhavefulfilledtheinclusion studycriteria.Themeanageofthepatientswas58.03±12.16 years.The RA duration median was 144 monthswith the interquartilerangefrom84to288months,whilethe symp-tomsdurationmedian(pain,limitedmobility)causedbythe RAwas159.5monthswiththeinterquartilerangefrom 107 to240months.Durationmedianofthecurrent RAtherapy was60monthswiththeinterquartilerangefrom24 to108 months. The median of the time passed from the begin-ningofthesymptomscausedbytheRAuntilallcurrentRA therapiesstartwas68.5monthswiththeinterquartilerange from 24 to164 months,namely: (1) untilthe therapy with NSAIDsand/oranalgesicsand/orcorticosteroids(median=48 months;interquartilerangefrom13to201months);(2)until the therapy with synthetic DMARDs alone or in combina-tionwithcorticosteroidsand/orNSAIDs(median=49months; interquartilerangefrom12to151months);(3)anyRA treat-mentwhichincludesbiologicDMARDs(median=99months; interquartilerangefrom46to166months).Theaveragevalue oftheFASscorewas27.31±8.81.ThemeanvalueofthePHQ-9 scorewas10.13±7.00andoftheGAD-7scorewas8.21±6.11. Descriptionofdemographicandsocioeconomicvariables ispresentedinTable1.InTable2thecategoriesofthetherapy variablesweredescribed.

Onehundredandninetyseven(48.14%)patientshadthe PHQ-9score≥10.ThesamenumberalsohadtheFASscore

≥22,while148(36.19%)patientshadtheGAD-7score≥10.The descriptivestatisticsforthedurationofthedisease,difficulties

Table1–Descriptionofdemographicandsocioeconomic variablesinstudypopulationofpatientswith

rheumatoidarthritis(n=409).

Variables f(%)

Gender

Female 356(87.0)

Male 53(13.0)

Occupation

Worker 46(11.3)

Farmer 5(1.2)

Housewife 53(13.0)

Official 41(11.7)

Pensioner 227(53.7)

Unemployed 37(9.0)

Formaleducationlevel

Withoutschool 7(1.6)

Elementaryschool 89(21.9)

Secondaryschool 146(35.8)

College 98(23.9)

Faculty 69(16.8)

Maritialstatus

Married 274(67.0)

Unmarried 32(7.9)

Divorced 28(6.9)

Widow/widower 67(16.4)

Extramaritalcommunities 8(1.8)

Employmentstatus

Employed–abletowork 82(20.1)

Employed–disableduetoRA 13(3.2)

Unemployed–workingcapable 61(15.0)

Unemployed–disableduetoRA 26(6.3)

Retired 227(55.4)

Needofanotherperson’sassistance

Yes 178(43.5)

No 231(56.5)

Frequenttaxiuse

Yes 182(44.6)

No 227(55.4)

Self-paymentofphysiotherapist

Yes 106(25.9)

No 303(74.1)

Theuseofassistivedevices

Yes 96(23.5)

No 313(76.5)

Otherdiseases

Withoutotherdiseases 174(42.5)

Withotherrheumaticdisease 22(5.5)

Withothernon-rheumaticdisease 213(52.0) Osteoporosis

Yes 139(34.0)

No 270(66.0)

OrthopedicsurgeryforRA

Yes 105(25.7)

No 304(74.3)

FracturesduetoRA

Yes 65(15.8)

No 344(84.2)

RA,rheumatoidarthritis;f,frequency.

duration,currenttherapyandtheperiodfromthebeginning

ofthesymptomsuntilthecurrentRAtherapystartwiththe

levelofdifferencesignificancebetweenthegroupsofpatients

withtheabsenceandthegroupofpatientswiththepresence

ofhighdepression,anxietyandthehighfatiguearepresented

Table2–Therapyvariablesdescriptioninstudypopulationofpatientswithrheumatoidarthritis(n=409).

Variables f(%)

ThecurrentRAtherapy

NSAIDsand/oranalgesicsand/orcorticosteroids 51(12.5)

SyntheticDMARDsaloneorincombinationwithcorticosteroidsand/orNSAIDs 198(48.4)

AnyRAtreatmentwhichincludesbiologicDMARDs 160(39.1)

Proton-pumpinhibitors

Yes 273(66.8)

No 136(33.2)

HistamineH2receptorantagonist

Yes 117(28.5)

No 292(71.5)

Supplementofglucosaminesulphate,chondroitinsulphate,hyaluronicacid

Yes 56(13.6)

No 353(86.4)

Antirheumaticcreams

Yes 239(58.5)

No 170(41.5)

VitaminD3

Yes 279(68.2)

No 130(31.8)

Calciumsupplements

Yes 175(42.9)

No 234(57.1)

PatientsdiscontinuationofRAtherapy

Yes 75(18.4)

No 334(81.6)

Bleedingfromthestomachorduodenumortheappearanceof“blackstool”duringRAtherapy

Yes 45(10.9)

No 364(89.1)

Operationsduetobleedingfromthestomachorduodenumortheappearanceof“blackstools”

Yes 18(4.4)

No 391(95.6)

UseofalternativemethodsofRAtreatment

Yes 52(12.7)

No 357(87.3)

RA,rheumatoidarthritis;NSAIDs,non-steroidalanti-inflammatorydrugs;DMARDs,disease-modifyingantirheumaticdrugs;f,frequency.

ItwasestimatedthatthePHQ-9score,theFASscoreand

theGAD-7scorecategoryvariablesstatisticallysignificantly

correlatewiththe majorityofsocioeconomicvariables and

comorbidity, except for gender, marital status and

ortho-pedic intervention (Table 4). In addition, the GAD-7 score

categoryvariablehasnotshownacorrelationwithbone frac-ture.Also,itwasnoticedthatthePHQ-9score,theFASscore and the GAD score statisticallysignificantly correlate with mostofthe therapy variables,exceptforthe self-initiative discontinuationoftheRAtherapyandthealternative ther-apyuse(Table5).Aditionally,the PHQ-9scoreandthe FAS scorehavenotshownasignificantcorrelationwiththe vita-mine D3 therapy, while the FAS score has not correlated withtheantirheumaticcreamuseandwiththeoperationin gastrointestinal tract causedby bleeding.The GAD-7score categoryvariable also hasnot showna significant correla-tionwiththeantirheumaticcreamuse,aswellasthecalcium therapy.

Bythelogisticregressionmodelitwasdemonstratedthat thehighdepressionwasrelatedtofiveindependent predic-tors(Table6).Thesignificantpredictorofthehighdepression wasthesyntheticDMARDstherapyaloneorcombinedwith the corticosteroids and/or NSAIDs. The sociodemographic

predictors of the PHQ-9 score ≥10 were physiotherapist self-payment, frequent taxi use, alternative treatment and employmentstatus.Twocategoriesoftheemployment sta-tushaveshowntobesignificantpredictorsofthePHQ-9score

≥10.Those arethe categoryofunemployed but capableto work,andthecategoryofunemployedasadisabledperson duetotheRA.Thankstothementionedpredictorsthe70.2%of thetotalvariabilityofthedependentvariablewasexplained, so thevariability ofthe presenceofthehigh depressionis explainedby75.5%,whilethevariabilityoftheabsenceofthe highdepressionisexplainedby65.3%.

Table3–Descriptivestatisticsforthedurationofthediseaseandsymptomsandcurrenttherapydurationfromthe appearanceofsymptomstothestartofcurrenttherapyofrheumatoidarthritisaccordingtotheabsence/presenceof highdepression,highfatigueandhighanxietyinstudypopulationofpatientswithrheumatoidarthritis.

Variables Outcome Percentiles p

25 50 75

ThedurationofthecurrentRAtherapy(months) PHQ ≥ 10absence 18.00 53.00 84.00 0.001 PHQ ≥ 10presence 36.00 72.00 120.00

RAduration(months) PHQ ≥ 10absence 84.00 120.00 204.00 0.008

PHQ ≥ 10presence 96.00 168.00 240.00

TheperiodfromthefirstappearanceofRAsymptoms tothestartofthecurrentRAtherapy(months)

PHQ ≥ 10absence 25.50 66.00 151.50

0.645 PHQ ≥ 10presence 24.00 73.00 183.50

DurationofsymptomsduetoRA(months) PHQ ≥ 10absence 90.00 145.00 221.00 0.006

PHQ ≥ 10presence 112.50 180.00 263.50

ThedurationofthecurrentRAtherapy(months) FAS≥ 22absence 18.00 48.00 77.00 0.000

FAS≥ 22presence 24.50 61.50 120.00

RAduration(months) FAS_FAS≥ 22absence 84.00 120.00 186.00 0.012

≥ 22presence 96.00 156.00 240.00

TheperiodfromthefirstappearanceofRAsymptoms tothestartofthecurrentRAtherapy(months)

FAS≥ 22absence 27.00 60.00 144.00

0.749

FAS≥ 22presence 24.00 73.00 181.00

DurationofsymptomsduetoRA(months) FAS≥ 22absence 88.00 144.00 210.00 0.013

FAS≥ 22presence 108.00 177.00 263.50

ThedurationofthecurrentRAtherapy(months) GAD ≥ 10absence 20.00 60.00 84.00 0.002 GAD ≥ 10presence 36.00 72.00 120.00

RAduration(months) GAD ≥ 10absence 84.00 144.00 204.00 0.015

GAD ≥ 10presence 96.00 168.00 240.00

TheperiodfromthefirstappearanceofRAsymptoms tothestartofthecurrentRAtherapy(months)

GAD ≥ 10absence 25.00 72.00 161.00

0.018 GAD ≥ 10presence 24.00 66.00 189.00

DurationofsymptomsduetoRA(months) GAD ≥ 10absence 93.00 152.00 228.00 0.790

GAD ≥ 10presence 122.00 180.00 274.50

PHQ-9,PatientHealthQuestionnaire;FAS,FatigueAssessmentScale;GAD-7,GeneralizedAnxietyDisorder;RA,rheumatoidarhtritis.

Thesignificantpredictorofthehighanxietyinthelogistic

regression model were proton pump inhibitor

gastropro-tection and two occupation categories – housewife and

pensioner(Table6)andthesepredictorsexplained64.8%of

totalpensionerofthedependentvariable.Thevariabilityof thepresenceofthehighanxietywasexplainedwith13.5%, while the explained pensioner of absence of the severe anxietywas93.9%.

Thelinearregressionmodelresultedinthestatistically sig-nificantcorrelationofthePHQ-9scorewiththeGAD-7and the FASscores. That waspresentedbythe equation: PHQ-9score=−3.47+0.634×GAD-7score+0.323×FASscore.The multiplelinearregressionmodelstatisticsforthepredictors were:(1)fortheconstant(t=−0.784;p=0.000);(2)forthe GAD-7score(t=0.548;p=0.000)and(3)fortheFASscore(t=0.402; p=0.000).Thedeterminationcoefficient(R2_{)forthementioned} linearmodelwas0.788.Therewasastatisticallysignificant changeoftheR2_{forthementionedlinearregressionmodel} withtheFASscoreandGAD-7scorepredictorsforPHQ-9score incomparissonwithmodelthatcontainsonlytheGAD-7score (Fchanges=124.979;df1=1;df2=408;p=0.000).TheR2_ofthe modelthatcontainedtheGAD-7score,astheonlypredictor ofthePHQ-9was0.716.Thebiggestconditionalindexinthe

linearregressionmodelwithtwopredictorswas10.021.The VIFvaluesinbothpredictorswereidenticalandwere2.221.

Discussion

Accordingtothesocialsignaltransductiontheoryof depres-sion,the lowsocioeconomicstatusimpliesthehigh riskof socialconflicts,socialisolation,excludingorrejectinga per-son,andalsorepresentsoneofthemostimportantprovoking factorsorbigstressfullifeeventsthatcausethemajor depres-sionand stimulationofinflammation.26 _{InRApatientsthe}

interpersonal lossand the socialisolation are the key fac-torsthatcanleadtothediseaseexacerbationcausedbythe inflammationortotheadditionaldepressionsymptoms exac-erbationandtheappearanceofthemajordepression.27_Our

Table4–Correlationsbetweencategoriesofdemographicandsocioeconomicvariablesandvariablesofcomorbidity withabsence/presenceofhighdepression,fatigueandanxietyinpatientswithrheumatoidarthritis.

Variables PHQ-9score≥10

Correlation(p)

FASscore≥22 Correlation(p)

GAD-7score≥10 Correlation(p)

Absence n1=212

Presence n2=197

Absence n1=212

Presence n2=197

Absence n1=212

Presence n2=197

Gender

Female −0.082(0.101) −0.072(0.136) −0.067(0.165)

Male Occupation

Worker Farmer Housewife

Official 0.341a_{(0.000) 0.273}a_{(0.000) 0.229}a_(0.000)

Pensioner Unemployed

Formaleducationlevel

Withoutschool Elementaryschool

Secondaryschool 0.329a_{(0.000) 0.323}a_{(0.000) 0.259}a_(0.000)

College Faculty

Maritialstatus

Married Unmarried

Divorced 0.130(0.148) 0.138(0.083) 0.141(0.077)

Widow/widower

Extramaritalcommunities

Employmentstatus

Employed–abletowork Employed–disableduetoRA

Unemployed–workingcapable 0.302a_{(0.000) 0.267}a_{(0.000) 0.209}a_(0.003)

Unemployed–disableduetoRA Retired

Needofanotherperson’sassistance

Yes −0.368a_(0.000) −0.369a_(0.000) −0.271a_(0.000)

No

Frequenttaxiuse

Yes −0.346a_{(0.000) −0.282}a_{(0.000) −0.246}a_(0.000)

No

Self-paymentofphysiotherapist

Yes −0.312a_{(0.000) −0.224}a_{(0.000) −0.229}a_(0.000)

No

Theuseofassistivedevices

Yes −0.290a_{(0.000) −0.199}a_{(0.000) −0.186}a_(0.000)

No

Otherdiseases

Withoutotherdiseases

Withotherrheumaticdisease 0.190a_{(0.001) 0.214}a_{(0.000) 0.152}a_(0.007)

Withothernon-rheumaticdisease

Osteoporosis

Yes −.173a_{(0.001) −0.156}a_{(0.002) −0.182}a_(0.000)

No

OrthopedicsurgeryforRA

Yes 0.117(0.083) 0.049(0.632) 0.113(0.088)

No

FracturesduetoRA

Yes −0.110b_{(0.031) −0.134}a_{(0.007) −0.078(0.116)}

No

PHQ-9,PatientHealthQuestionnaire;FAS,FatigueAssessmentScale;GAD-7,GeneralizedAnxietyDisorder;RA,rheumatoidarthritis.

a _{Levelofstatisticalsignificanceforp≤0.01.}

Table5–Correlationsbetweencategoriesoftherapywithabsence/presenceofhighdepression,fatigueandanxietyin patientswithrheumatoidarthritis.

Variable PHQ-9score≥10

Correlation(p)

FASscore≥22 Correlation(p)

GAD-7score≥10 Correlation(p)

Absent n1=212

Present n2=197

Absent n1=254

Present n2=155

Absent n1=212

Present n2=197

ThecurrentRAtherapy

NSAIDsand/oranalgesicsand/orcorticosteroids SyntheticDMARDsaloneorincombinationwith corticosteroidsand/orNSAIDs

0.228a_{(0.000) 0.223}a_{(0.000) 0.193}a_(0.000)

AnyRAtreatmentwhichincludesbiologicDMARDs

Proton-pumpinhibitors

Yes −0.137a_{(0.007) −0.145}a_{(0.003) −0.116}b_(0.019)

No

HistamineH2receptorantagonist

Yes −0.157b_(0.011) −0.131b_(0.037) −0.165a_(0.005)

No

Supplementofglucosaminesulphate,chondroitinsulphate,hyaluronicacid

Yes 0.161a_{(0.008) 0.111(0.090) 0.122(0.055)}

No

Antirheumaticcreams

Yes −0.191a_{(0.000) 0.131}b_{(0.027) 0.137}b_(0.021)

No

VitaminD3

Yes 0.023(0.644) 0.031(0.523) −0.104b_(0.039)

No

Calciumsupplements

Yes −0.140a_{(0.004) −0.110}b_{(0.025) −0.065(0.230)}

No

PatientsdiscontinuationofRAtherapy

Yes −0.065(0.230) −0.045(0.395) −0.082(0.116)

No

Bleedingfromthestomachorduodenumortheappearanceof“blackstool”duringRAtherapy

Yes −0.243a_{(0.000) 0.120}b_{(0.014) 0.139}a_(0.005)

No

Operationsduetobleedingfromthestomachorduodenumortheappearanceof“blackstools”

Yes −0.154a_{(0.003) −0.057(0.246) −0.113}b_(0.024)

No

UseofalternativemethodsofRAtreatment

Yes 0.079(0.122) −0.055(0.271) 0.043(0.385)

No

PHQ-9,PatientHealthQuestionnaire;FAS,FatigueAssessmentScale;GAD-7,GeneralizedAnxietyDisorder;RA,rheumatoidarthritis;NSAIDs, non-steroidalanti-inflammatorydrugs;DMARDs,disease-modifyingantirheumaticdrugs.

a _{Levelofstatisticalsignificanceforp≤0.01.}

b _{Levelofstatisticalsignificanceforp≤0.05.}

socialrejection,isolationand interpersonallossduetothe disability.Otherauthorsalsofoundthatthebad socioecono-micstatusincreasesthedepressionsymptomsmeasuredby PHQ-9surveyinRApatients.28_{Löweetal.demonstratedthat}

thedepressionisasignificantpredictoroftheworking inca-pabilityoftheRApatients.29 _{Inourstudy,othersignificant}

socioeconomicpredictors ofthehighdepressionwere: pen-sionerstatus,unemploymentoftheworkingcapablepatients, frequenttaxiuse,self-paymentofphysiotherapistand self-paymentofalternativetreatment.Thelastmentionedfactors alsoimplyabadsocioeconomicRApatients’statusduetothe lackofthe incomeorinsufficientpersonalincome,aswell astheiradditionalfinancialexhaustionbytheexpensesthey haveontheirownduringthedailyactivities,implementation ofphysiotherapymeasurementsorthealternativetreatment or someother activities requiredatthe rehabilitaion, pain

reliefandtheimprovementofthesocialfunctioningin gen-eral.

Wealsoshowedthat,ingeneral,theRAtherapyhasno influence on the appearance ofthe high depression inRA patients,butthereisasignificantinfluenceofthesynthetic DMARDtherapycategoryaloneorcombinedwith corticoste-roidsor/andNSAID.Inourstudypopulationpatientswiththe aforementionedtreatmentmodalitywere80%morelikelyto haveahighdepression,whichpotentiallyindicatesahigher RAactivity inthese patients.Itwasdemonstratedinsome longitudinalstudiesthatpersistentdepression/anxiety symp-tomspredictpoortreatmentresponsewhichcorrespondswith increasedRAactivityovertime.30_{Inaunivariateanalysisof}

Table6–Logisticregressionmodelsparametersaccordingtosociodemographic,socioeconomicandtherapeutic predictorsofhighdepression,fatigueandanxietyinpatientswithrheumatoidarthritis.

Examinedoutcome–PHQ-9score ≥ 10 95.0%Confidenceinterval

Predictors B SE Wald df p oddsratio lower upper

ThecurrentRAtherapy 4.982 2 0.083

NSAIDsand/oranalgesicsand/or corticosteroids

0.324 0.447 0.525 1 0.469 1.383 0.575 3.323

SyntheticDMARDsaloneorin combinationwithcorticosteroids and/orNSAIDs

0.630 0.283 4.972 1 0.026 1.878 1.079 3.269

Self-paymentofphysiotherapist 1.250 0.349 12.841 1 0.000 3.490 1.762 6.914

Employmentstatus 18.117 4 0.001

Employed–disableduetoRA 0.404 0.864 .218 1 0.640 1.498 0.275 8.151

Unemployed–workingcapable 1.357 0.435 9.731 1 0.002 3.884 1.656 9.111

Unemployed–disableduetoRA 1.900 0.697 7.423 1 0.006 6.687 1.704 26.238

Retired 1.384 0.354 15.252 1 0.000 3.989 1.992 7.989

Frequenttaxiuse 0.785 0.275 8.179 1 0.004 2.193 1.280 3.755

UseofalternativemethodsofRA treatment

0.772 0.385 4.024 1 0.045 2.164 1.018 4.600

Constant −2.756 0.493 31.274 1 0.000 0.064

Examinedoutcome–FASscore≥ 22 95.0%Confidenceinterval

Predictors B SE Wald df p oddsratio lower upper

Needofanotherperson’sassistance 1.102 0.384 8.220 1 0.004 3.009 1.417 6.389

GAD-7score 0.320 0.048 43.986 1 0.000 1.377 1.253 1.514

Calciumsupplements 0.855 0.357 5.738 1 0.017 2.352 1.168 4.736

Age>65godina −1.031 0.478 4.653 1 0.031 0.357 0.140 0.910

Formaleducationlevel 13.994 4 0.007

Withoutschool 17.112 18,629.741 0.000 1 0.999 27,004.818 0.000

Elementaryschool 0.270 0.530 0.259 1 0.611 1.310 0.463 3.702

Secondaryschool 1.589 0.452 12.389 1 0.000 4.901 2.023 11.876

College 0.693 0.474 2.142 1 0.143 2.000 0.790 5.062

Constant −1.532 0.586 6.837 1 0.009 0.216

Examinedoutcome–GADscore≥ 10 95.0%Confidenceinterval

Predictors B SE Wald df p oddsratio lower upper

Occupation 17.908 5 0.003

Farmer −0.024 1.207 0.000 1 0.984 0.976 0.092 10.400

Housewife 1.245 0.448 7.717 1 0.005 3.474 1.443 8.366

Official −0.719 0.590 1.486 1 0.223 0.487 0.153 1.548

Pensioner 0.837 0.370 5.121 1 0.024 2.309 1.119 4.766

Unemployed 0.675 0.489 1.901 1 0.168 1.963 0.752 5.123

Proton-pumpinhibitors 0.491 0.238 4.248 1 0.039 1.634 1.024 2.608

Constant −1.566 0.382 16.822 1 0.000 0.209

PHQ-9,PatientHealthQuestionnaire;FAS,FatigueAssessmentScale;GAD-7,GeneralizedAnxietyDisorder;RA,rheumatoidarthritis;NSAIDs, non-steroidalanti-inflammatorydrugs;DMARDs,disease-modifyingantirheumaticdrugs.

frequency.31_{However,inotherreportstherewasnoRA}

ther-apyinfluenceontheself-reportedhighdepressionfrequency intheRApatients.32_{Bothbeforeandduringthestudyperiod}

thecurrentbiologicdrugsprovidedbythehealthinsurance ofRepublicofSerbia,thatwereavailabletotheRApatients are humanproteindrugs thatneutralize pro-inflammatory effectsoftumornecrosisfactorandinterleukin-6.Theabove mentioned biologic drug combined with methotrexate is prescribedtotheRApatientswhosediseaseisstillclinically active(i.e.whoseDiseaseActivityScoreisabove5.1)despite theimplementationofmethotrexate(atleast15mgonce a

experience of disforia, hopelessness and uselessness, can alsobeoneofthe contextual,psychosocialtriggersforthe appearence of major depression and poor RA treatment response.

We also found that the RA therapy (Table 6) does not increasetheriskofthehighfatigueordepression,aswellas that the high fatigueand anxiety, completely independent onefromanother,leadtothehighleveloftheself-reported depressionsymptoms.Ontheotherhand,theresultsimply that the increase of the anxiety level also increases the risk of the high fatigue appearance. These are important factssincethereisnospecificpharmacotherapyofthehigh fatigue.Withalltheabovementioned,wehighlightthatthe specific medicamentous therapy should be implemented withantidepressantsthathaveastronganxiolyticeffect(for examplewithselectiveserotoninreuptakeinhibitors),bothin ordertoreducethedepressionsymptomsandtopotentially decreasethehighfatigueoftheRApatients.

Inourstudytheageabove65yearshadaprotectiveeffect ontheappearanceofthehighfatigueinRApatients.Thiskind offindingcoexistswiththefindingsofWattetal.,whoshowed that,dependingontheage,fatigueinthegeneralpopulation hasanon-lineartrend.33_{Inthegeneralpopulationaglobal}

fatigueevaluationaftertheageof65wasdecreasingbecause ofthementalandcognitivefatiguecomponentdecrease. How-ever,thestudiesintheRApatientspopulationsdidnotshow anychangesinthefatiguelevelwiththechangeofage.34

Wealsodemonstratedthatcalciumsuplementation ther-apy for prophylaxis or therapy of osteoporosis in the RA patientscansignificantlyincreasetheriskofthehighfatigue appearance.This potentially suggests thatcalcium supple-ments therapy in our patients was administered without adequatemonitoringofserumionizedcalcium.Fatigueisvery commonsymptomofhypercalcemia.35_{Oelzneretal.reported}

thatabout30%oftheRApatientshavehypercalcemia(high levelsofserum ionizedcalcium) thatoccurs inassociation withthe highdisease activity,suppressedparathyroid hor-monesecretion,suppressedvitaminDhormonesynthesisand bonemineraldensityreduction.36

From socioeconomicfactors the importantpredictors of thehighfatigueintheRApatientsweretheneedforother peo-ple’shelpandcare,aswellastheleveloftheformaleducation thatisdefinedasfinishedcollegeeducation.InSerbiaformal educationtoobtainacollegedegreelastsfor12years. Castre-jonetal.foundthattheRApatientswithaformaleducation lastinglessthanorexactly12yearshadthebiggerfatigue com-paredtothepatientswithformaleducationthatlastedmore than 12years.37 _{Theneed forother people’shelpand care}

impliessomeseveresetbackandtheseRApatients’problemin performingdailyactivities.Inotherstudiesitwasshownthat therestrictionofdailyactivitiescorrelatespositivelywiththe fatigue,andthattheincreaseofthedailyactivitiescorrelates negativelywiththefatigue.38,39

Whenitcomestothesocioeconomicpredictorsofthehigh anxietyinourstudypopulation,the significantriskfactors weretwocategoriesofoccupation–pensionerandhousewife (Table6).Itisdescribedintheliteraturethatthehousewives withthemilderRAweremoreanxiouseventhoughtheyhad theirspouse’sunderstandingfortheirdisease.40_Patientswith

thespecificoccupationcategorieswhosesociallifeismostly

spentinthehouseormostlyrelatedtothehouseand fam-ilysurroundings canpossiblyexperience moreanxietythat isinversely relatedtothe RAseverityand theexperienced understandingbythepersonswithwhomtheylive.

Additionally,theriskfactorofthehighanxietyappearance was alsoastomachbleedingpreventionbythe PPI.In Ser-bia,unlikethedrugsfromtheH2antagonistgroupwhichare cheap,theRApatientshavetopayforthePPIgastroprotecive therapybythemselvesswhichisveryexpensiveforthem.The fearwhether andhowlong theywillbeabletopayforthe PPI,forthegastroprotectioncanalsobeariskfactorofthe highRApatients’anxiety.Therestofthesocioeconomicand therapypredictorsinthisstudy(Tables4and5)haveshown, inspiteoftheachievedstatisticalsignificance,aweak corre-lationwiththeself-reportedoutcomesofthepatients.These predictorsshareasmallmutualvarianceofallthreeoutcomes (depression,fatigueandanxiety),whichimpliesthattheyare notspecificforanyofthem.

The limitations of our study primarily originate from its design. A cross sectional study designdoes not evalu-atethespecificsofthequestionedpredictors’influenceson theappearanceofthefatigue,depressionandanxetyinRA patients, comparedto thepatient populationwith another inflammatory or non-inflammatory disease. In our study, theRAactivitywasnotmonitoredandthereforewecannot excludecertainbiasinourexplanationsoftherelationship betweentheappearanceofthehighdepressionandtreatment responses.Sincewehavenotmonitoredthestatusofcalcemia and/orRAactivity,therealsomaybesomebiasinour explana-tionofthelinkbetweenthehighfatigueandcalciumtherapy. Eventhoughwehadalargepatientspopulationinthestudy, themalepopulationresponsenumberwasunusuallysmall. Consequently,comparedtothefemalepopulation,observed riskfactorsoftheappearanceofthequestionedself-reported outcomesthatcomefromthemalepopulationarepotentially lessanalyzed.Also,inourRApatientpopulationwehaven’t recordedanydataabouttheuseofantidepressant,sedative and/oranxiolyticdrugs.

Conclusion

Demographic,socioeconomicandpsychosocialfactors,along with contextualand treatment factors, canlargely explain the appearanceofthe high levelofdepression andfatigue andhighanxietyinrheumatoidarthritispatients.The evalua-tionofthepsychosocial,socioeconomicandtherapyimpacts, along withtherheumatoidarthritisactivity and inflamma-tionontheappearanceofthehighdepression,highfatigue andhighanxietycanbeofgreatimportanceinfuturestudies inrheumatoidarthritispatients.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

theirgenuineengagementintheorganizationofthisstudy.We arealsothankfulforlinguisticcorrectionsofthemanuscript texttoAnaVukovi´c,languageandliteratureprofessor.

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