Rosacea associated with increased risk of generalized anxiety disorder: a case-control study of prevalence and risk of anxiety in patients with rosacea,

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Anais

Brasileiros

de

Dermatologia

www.anaisdedermatologia.org.br

INVESTIGATION

Rosacea

associated

with

increased

risk

of

generalized

anxiety

disorder:

a

case-control

study

of

prevalence

and

risk

of

anxiety

in

patients

with

rosacea

夽,夽夽

Pinar

Incel

Uysal

∗

,

Neslihan

Akdogan

,

Yildiz

Hayran

,

Ayse

Oktem

,

Basak

Yalcin

DermatologyDepartment,AnkaraNumuneTrainingandResearchHospital,Ankara,Turkey

Received30January2019;accepted28March2019 Availableonline26October2019

KEYWORDS Anxiety; Anxietydisorders; Depression; Rosacea Abstract

Background: Rosaceamayresultinemotionaldistressandanxiety.However,dataonthe pres-enceofgeneralizedanxietydisorderinrosaceapatientsarescarce.

Objective: Theaimofthestudywastodetectthefrequencyandlevelofanxietyanddepression inpatientswithrosacea.

Methods: Atotalof194consecutiverosaceapatientsand194age-andsex-matchedcontrols wereenrolled.Severity ofrosacea wasassessed inpatients accordingtothecriteriaofthe National Rosacea Society Ethics Committee.Both patients and controlswere evaluated by theGeneralizedAnxietyDisorder7-itemscale,andseveritywasmeasuredbytheGeneralized AnxietyDisorder-Adult.

Results: Individualswhowerediagnosedwithananxietyand/ordepressivedisorderweremore commoninpatientgroup(24.7%vs.7.2%,p<0,01).Femalepatientswereparticularlyatrisk forhavinggeneralizedanxietydisorder(OR=2.8;95%CI1.15---7.37;p=0.02).

Studylimitations: Singlecenterstudyandlimitedsamplesize.

Conclusions: Rosacea patients show greaterrisk ofhaving anxietydisorders, including gen-eralizedanxiety disorder.Female patients,those withlower educationallevels, thosewith phymatoussubtype,untreatedpatients,andpatientswithpriorpsychiatricmorbiditymaybe atparticular riskfor anxiety. Itisessential toconsider thepsychologicalcharacteristicsof patientstoimprovetheirwell-being.

夽 _How_to_cite_this_article:_Incel_Uysal_P,_Akdogan_N,_Hayran_Y,_Oktem_A,_Yalcin_B._Rosacea_associated_with_increased_risk_of_generalized

anxietydisorder:acase---controlstudyofprevalenceandriskofanxietyinpatientswithrosacea.AnBrasDermatol.2019;94:704---9.

夽夽_Study_conducted_at_the_Ankara_Numune_Training_and_Research_Hospital,_Ankara,_Turkey. ∗_{Corresponding}_author.

E-mail:pinarincel@hotmail.com(P.IncelUysal).

https://doi.org/10.1016/j.abd.2019.03.002

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Introduction

Rosaceaisachronicskindisordercharacterizedby inﬂam-matorypapules,telangiectasias,andfacialerythema,which can result in psychosocial consequences and emotional distress.Remissionsandexacerbationsaremajor character-isticsofthedisease.Originally,fourvariantsofrosaceawere describedbytheNationalRosaceaSocietyEthicsCommittee (NRSEC) as follows: erythematotelangiectatic, papulopus-tular, phymatous, and ocular form.1 _In _2017, _the _NRSEC

reportedupdateddiagnosticcriteriaforrosacea.2_The

com-mitteehasproposedastandardgradingsystemforrosacea, a clinical scorecard for rosacea, which provides a practi-calandusefultoolforclinicalpracticeaswellasresearch studies.1

Patientswithrosaceaaremorelikelytohavedepression, low self-esteem, social phobia, and stress.3---5 _Depression

is common among patients with rosacea and there is a direct relationship between rosacea severity and depres-sionseverity.6,7 _The _persistent _facial_erythema _of _rosacea

iscausedbyvasodilatationduetoautonomicnervesor cir-culatingvasoactivesubstances.Becausethereisnooptimal and effective treatment modality for persistent redness, patientsarepronetohavedecreasedqualityoflife(QoL). Also,ithasbeen shownthatsubjects withsevere rosacea had worse mean Dermatology Life Quality Index (DLQI) scoresthansubjectswithmilderforms.8

Afewstudieshavesuggestedthatrosaceapatientshave increasedriskofanxietydisorders.7,9_Although_the_available

evidenceaboutthepresenceofanxietydisordersinpatients withchronic dermatologicdiseasesincludingacne, psoria-sis,andvitiligoisrelativelyclearinstudies,thisassociation hasnotbeensufﬁcientlyaddressedinrosacea.Thepresent case---controlstudyaimedto(i)estimatefrequencyof co-morbiddepressionandanxietyamongrosaceapatients,(ii) identifygradeofanxietyinrosaceapatientsbythe Gener-alized Anxiety Disorder 7-itemscale (GAD-7) and severity measured bytheGeneralized AnxietyDisorder-Adultscale (GAD-Adult);(iii)todeterminewhetherthereisarelation betweenrosaceagradeandanxietygrade.

Methods

Studydesignandpatients

Thiswasacross-sectional,single-centercase---controlstudy withprospectiverecruitmentofpatientsandmatched con-trolsubjectsinatertiaryclinic. Consecutivepatientswho werediagnosedwithrosaceaduringtheperiodbetween Jan-uary2017andDecember2017wereincluded inthestudy. Therewere194patientsandage-andsex-matchedcontrols includedinthisstudy.Thecontrolgroupconsistedofhealthy volunteerswhopresentedwithcosmeticcomplaints.

Allparticipantswere18yearsofageor older.Allcases were subjected tosystemic and dermatological examina-tion.Exclusioncriteriaforthestudyandcontrolgroupwere asfollows:ageyoungerthan18,andpatientshavingchronic systemicillnesses,chronicinﬂammatorydermatological dis-eases,orcognitiveimpairment.

Datacollectionandmeasurements

Demographical and clinical data of the subjects were recorded.Allpatientswithrosaceawereexaminedbythe samedermatologistandclassiﬁedintofoursubtypes accord-ingtothestandardNRSECclassiﬁcationcriteria.1_The

clini-calscorecardconsistedofprimaryandsecondarysymptoms of patients (ﬂushing, nontransient erythema, telangiecta-sia, burning/stinging, plaques, dryness, edema), and The physician’sglobalassessment(IGA)andthepatient’sglobal assessment(PGA).Scoresfrom0to3areassignedtoeach category and all scores are summed to obtain a single totalscore(0---48). Rosacea severityscores ofall patients wererecordedbythesamedermatologistasabsent,mild, moderate, or severe. Smoking and drinking habits were also noted. The rosacea clinical scorecard (available at

https://www.rosacea.org/physicians/scoreindex.php) was

completedforeach patient.Patientsandcontrolsubjects self-reporting anysymptoms or previous clinical diagnosis of depression and/or anxiety were recorded. All patients were asked about presence of exacerbation or triggering of rosacea lesions with psychological stress. The medical historyofsubjectswasalsonoted.

TheGAD-7scaleisavalidatedscreeningtoolanda mea-sure for screening anxiety disorders includinggeneralized anxietydisorder,panicdisorder,andsocialanxietydisorder inthegeneralpopulation.10,11 _Total_GAD-7 _scores_are

pre-sented from0 to21. The totalscore is a guide toassess severityoftheanxietyasfollowing:<5mildanxiety;5---10 moderateanxiety;>10severeanxiety.Inaddition,the sever-itymeasureofthe GAD-Adultisaten-itemmeasuretobe completedonascaleof0(never)to4(allofthetime)for assessing the severity of anxiety symptoms in individuals aged18 andolder.12 _Each _item_asks_the_severity_of

symp-tomsduringpastsevendays.Therawtotalscorecanrange from0to40.Theaveragetotalscoreisaﬁve-pointscale, whichallowstocliniciantojustifytheseverityofthe anx-iety disorder of the individual as follows: none (0), mild (1),moderate (2),severe (3), or extreme (4). The GAD-7 questionnaire andthe severity measure of the GAD-Adult weredevelopedbasedonDiagnosticandStatisticalManual ofMentalDisorders(DSM)IVandVcriteria,respectively.

All patients and control subjects completed the GAD-7 and the severity measure of the GAD-Adult (Table 1) toscreen for anxiety disorders. Dataof the patients who hadrepetitiveadmissionswereincludedonlyonce. Incom-pletequestionnairesorpatientswithincompletedatawere excluded.

Statistics

StatisticalanalyseswerecarriedoutusingSPSSsoftware(v. 21.0 for Windows; SPSS Inc., Chicago, IL, United States). Parametricvariableswereexpressedasmeansandstandard deviations,andnonparametricvariableswerepresentedas medians and interquartile ranges. For categorical varia-bles,thenumberofcasesandpercentageswereused.The Kolmogorov---Smirnovtestandhistogramanalyseswereused todetermine whethercontinuous variableswere normally distributed. Normally distributed numeric variables were analyzed by Student’s t-test and ANOVA. The chi-squared

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Table1 Comparisonofdemographiccharacteristicsofthestudyandcontrolgroups.

Patients(n=194) Controls(n=194) p-Value Sex,n(%)

Female 147(75%) 147(75%)

---Male 47(25%) 47(25%)

---Age,median(IQR)(years) 47(40---56) 46(39---54.25)

---Habitofcigarettesmoking,n(%)

Currentsmoker 41(21.1%) 58(29.9%) p=0.005

Ex-smoker 22(11.3%) 7(3.6%) p=0.005

Neversmoked 131(67.5%) 129(66.5%) p>0.05

Pack-yearsofcigarettesmoking(mean±SD) 15.5±1.2 12.4±0.9 p>0.05

Alcoholconsumption,n(%) p>0.05 Everused 172(88.7%) 160(82.4%) Lastweek 16(8.2%) 17(8.7%) Lastmonth 6(3%) 17(8.7%) Educationallevel,n(%) p<0.001 Elementaryschool 97(50%) 30(15.4%) Middleschool 24(12.3%) 50(25.7%) Highschool 46(23.7%) 69(35.5%) University 10(5.1%) 37(19%) Noeducation 17(8.7%) 8(4.1%)

IQR,interquartilerange;SD,standarddeviation.

test or Fischer’s exact test wereused for analyzing cate-goricalvariables.Mann---WhitneyUandKruskal---Wallistests were performed for comparing non-normally distributed numericvariables.Correlations of numericvariableswere assessedby Spearman and Pearsontests. Multiplelogistic regression models were created to examine the relation-shipsbetweenstudyvariablesandtherecordedpsychiatric diagnosisandpresenceofgeneralizedanxietydisorder, pro-vidingodds ratios(OR) and 95%conﬁdence intervals (95% CI).Thelevelofsigniﬁcancewassetasp<0.05.

Results

Participantcharacteristics

The study enrolled 194 patients (147 female, 47 male) and194 age- and sex-matchedrosacea-free controls (147 female,47male).Themedianageofcaseswas47(ranging between18and74).Ex-smokersweremorecommonamong thepatientgroup.Alcohol intake(p=0.083)andcigarette consumption(p=0.59)werecomparablebetweencasesand controls. Having graduated fromhigh school or university wasmorecommonamongcontrolsubjects(p<0.001).The median value of educationallevel was elementaryschool amongpatients,whereasitwashighschoolincontrols.

Demographical and life stylecharacteristics and medi-calhistoryofstudy andcontrol groupsaresummarized in

Table1.

Rosaceacharacteristics

The erythematotelangiectatic subtype was the most fre-quent(58.9%) subtype,and the diseaseseverity wasmild

andmoderateinmostpatients(85.1%).Themedianrosacea severityscore ofthe patientswas12 (IQR:10---16), which correspondstothemildformofrosacea.Clinical character-isticsandvariablesofclinicalscorecardareshowninTable2. Asigniﬁcantpositivecorrelationwasfoundamongseverity scores, PGA(r=0.559; p<0.001),andthephysicianrating bysubtype(r=0.805;p<0.001).

Rosaceaandpsychosocialdisorders

Rosaceaandassociatedpsychosocialvariablesarepresented

inTable3.

Personalhistoryofpreviousdiagnosis ofananxiety dis-orderand/ordepressionwasmorefrequentamongpatient group(24.7%vs.7.2%;p<0.001).Theauthorsfounda signiﬁ-cantdifferenceinfrequencyofuseofmedicationprescribed foranypsychosocialdisorderbetweenpatientsandcontrols atthetimeofadmission(14.4%inpatientsvs.5.2%in con-trols;p=0.002).Intotal,3.6%ofpatientshadbothanxiety anddepressivedisorders,whereasnooneincontrolgroup had prior historyof both disorders.Patientswith rosacea weremorelikelytohaveanxietydisorders(OR=4.59;95% CI:1.69---12.43; p=0.003) anddepression (OR=3.041; 95% CI:1.38---6.07;p=0.006)(Table3).

ThemedianvaluesofGAD-7(p<0.001),theseverity mea-sureofGAD-Adultaverage(p<0.001),andrawtotalscores (p<0.001)werehigherinpatientsthancontrols(Table3).It wasobservedthat25%ofpatients(n=50)screenedpositive (GAD-7>9)forGAD comparedwith4.1%of controls(n=8;

p<0.05).Patientswithrosaceawerelikelytohave higher gradeofanxietythancontrolsubjects.

TherewerenocorrelationsbetweenPGA,physicians rat-ing by subtype (IGA) and anxiety scores (PGA and GAD

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Table 2 Disease characteristics of the patients with rosacea(n=194).

Clinicalcharacteristicsofthepatients n=194

Diseasesubtypesa_,_n_(%)

Erythematotelangiectatic 114(58.7%)

Papulopustular 95(48.9%)

Phymatous 9(4.6%)

Ocular 10(5%)

Durationofthedisease,median(IQR)(months) 36(12---72)

Treatmentmodalities,n(%)

None 43(22.2%)

Sunprotection 16(8.2%)

Topicaltreatments 82(42.3%)

Combinationoftopicalandoralantibiotics 37(19%)

Oralisotretinoin 16(8.2%)

Physiciansratingbysubtype,n(%)

Mild 133(68.5%)

Moderate 56(28.9%)

Severe 5(2.6%)

Patient’sglobalassessment,n(%)

Mild 64(33%) Moderate 89(45.9%) Severe 41(21%) Gradeofrosaceab_,_n_(%) Mild 77(39.7%) Moderate 88(45.4%) Severe 29(14.9%)

Severityscore,median(IQR) 12(10---16)

IQR,interquartilerange;SD,standarddeviation.

a _Some_patients_presented_with_mixed_forms_of_disease. b _Mild_group_(range:_0---14),_moderate_group _(range:_15---24),

severegroup(≥25).

totalscore:p=0.95,r=0.004;PGAandGADaverage total score:p=0.95,r=0.004;PGAandGAD-7:p=0.61,r=0.037; PGAand severityof anxiety:p=0.97, r=−0.003;IGA and GAD total score: p=0.17, r=−0.099; IGA and GAD aver-agetotalscore:p=0.25,r=−0.83;IGAandGAD-7:p=0.45,

r=−0.055;IGAandseverityofanxiety:p=0.32,r=−0.072).

Riskfactorsforanxiety

MedianscoresoftheGAD-7andtheseveritymeasureofthe GAD-Adult were comparable in erythematotelangiectatic and papulopustular types (p>0.05). However, phymatous rosacea patients represented higher levels of all anxi-ety scores (p<0.05). Female patients had higher anxiety scores and grades of anxiety severity than male patients (p<0.05). Additionally, patients withprior history of psy-chiatricmorbidity(anxietydisorderand/ordepression)had higherscoresthantheothers(p<0.05).Incomparisonwith others, patients who had reported ﬂaring rosacea symp-tomsinresponsetopsychologicalstressrepresentedhigher grades of anxiety severity (p<0.001 for the GAD-7, GAD-Adult average scores, GAD raw total scores, and anxiety severity).

Patientswithloweducationallevelshadhigheranxiety scores thanpatients with highereducational levels (GAD-7, GAD-Adult, and severity of anxiety) (p<0.05). There was a negative correlation between anxiety scores and educationallevelsofpatients(GAD-7:p=0.014,r=−0.13; GAD-Adulttotalscore:p=0.018;r=−0.12;GAD-Adult aver-agescore:p=0.018,r=−0.12;anxietyseverity:p=0.019,

r=−0.12). The proportions of the patients receiving dif-ferenttypesoftreatmentweresimilarintermsofanxiety scores(p>0.05).However,theuntreatedpatientswereat riskofhavingsevereanxiety(OR=2.07;95%CI:1.43---4.06;

p=0.04).There werenosigniﬁcant relationshipsbetween age, age of disease onset, disease duration, smoking, or drinkinghabitsandpresenceorseverityofanxiety.

Risk of GAD (GAD-7 item score>9) was signiﬁcantly increasedinfemales(OR=2.8;95%CI:1.15---7.37;p=0.02). Therewerenosigniﬁcantrelationshipbetweenage,ageof onset,educational status, disease duration,or treatment groupsandpresenceofGAD(p=0.18,p=0.49,p=0.65,and

p=0.22,respectively).

Discussion

Studieshaveshownthatpsychiatriccomorbiditiesand unde-tected psychopathologies can greatly impact the QoL of patientswithdermatologicaldisorders.Furthermore,these conditionsmay contribute to the clinical severity of skin disorders.Rosaceaisoneofthepsychosomaticskin condi-tionsthatcanﬂuctuateinaccordancewithemotionalstate.

Table3 GAD7-itemscaleandGAD-Adultscore,severityofanxiety,andpersonalhistoryregardingpsychosocialdisordersof

rosaceapatientsandcontrolsubjects.

Patients(n=194) Controls(n=194) p-Value

GAD-7score,median(IQR) 6(3---10) 2(0---3) <0.001

GAD-Adulttotalscore,median(IQR) 12(7---17) 3(1---8) <0.001

GAD-Adultaveragetotalscore,median(IQR) 1.2(0.7---1.7) 0.3(0.1---0.8) <0.001

Severityofanxiety,median(IQR) 1(1---2) 0(0---1) <0.001

Priorhistoryofpsychiatricmorbidity,n(%) 48(24.7%) 14(7.2%) <0.001

Anxietydisorder 21(10.8%) 5(2.6%) p<0.001

Depression 27(12.9%) 9(4.1%) p=0.004

Useofpsychiatricdrugatthetimeofdatacollection,n(%) 28(14.4%) 10(5.2%) p=0.002

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Accordingtothemostacceptedconsensusintheliterature, in case of emotional stress, the neuro-immuno-cutaneous system(NICS)isresponsiblefor releasingcytokines, medi-ators, and neurotransmitters contributing this complex interaction.13 _It _has _already _been _reported _that _patients

with rosacea have higher incidences of embarrassment, social anxiety, low-self esteem, and decreased DLQI.14

Besidesfeelingsofstigmatization,alltheseconditionsmay leadtodepressionoranxietydisorders.15

In the present study, past or recent history of psychi-atricillness anduse of psychiatricmedicationwere three tofourtimeshigher inpatients thancontrols. Of the194 patients,3.4%hadbeenpreviouslydiagnosedwithboth anx-iety disorder and depression. Obviously, patients were at higherriskofhavingpastorrecentdiagnosisofdepression oranxiety.Inlinewithotherstudies,rosaceaincreasedthe risk of both depression and anxiety.7,9 _The _present _study

demonstratedhigherGAD-7,GAD-Adultrawtotaland aver-agescores,andhighergradeofseverityofanxietyinrosacea patientsincomparisonwithcontrolsubjects.Furthermore, aconsiderablenumberofpatients(25%,n=50)had proba-blegeneralizedanxietydisordershownbytheGAD-7.Many of the studies addressing anxiety have mainly focused on social anxiety, and have used QoL and/or Hospital Anx-iety and Depression Scale (HDAS) measurements.9,16,17 _In

the literature search, the authors could not ﬁnd a study usingtheGAD-7andtheGAD-Adultquestionnairesinrosacea patients.Thus,thepresentstudyprovidesthesevalidscales formeasuringanxietygradeanddetectinggeneralized anx-ietydisorderinrosaceapatientsfortheﬁrsttime.

Aliniaetal.reportedadirectrelationshipbetween sever-ity of rosacea and degree of depression.18 _In _contrast,

the present study did not detect a correlation between anxiety scores or degree of anxiety and rosacea clinical score, PGA, and IGA. However, patients with phymatous rosacea had higher scores than the other subtypes. This resultsupportpreviousreports suggesting thatphymatous rosacea causes feelings of stigmatization and more over-allQoLimpairment.16,17_It_has_been_suggested_that_because

of mentend to experiencemore severe formsof rosacea thanwomen, they aremore proneto have social anxiety anddepression.15_Some_studies_discovered_that_males_were

morenegativelyaffected bythediseasethanfemales.16,19

However,inthepresentstudy,intheGAD-7andtheseverity of measure of the GAD-Adult, female patients had signi-ﬁcantlyhigher anxiety scores. Gender-related differences in the present study were consistent with some reports in the literature.7 _Of _note, _these _ﬁndings _may _be_clearly

explainedwiththefactthatfemalepatientsseemtofocus ontheimpactofrosaceaontheirappearance.Previous stud-iesrevealed thatyoungerpatients weremorelikelytobe affectedbyrosacea.16,20_However,_the_present_study_found

nocorrelation betweenageandrisk ofdepression or anx-iety. It has been shown that low socio-economical status is associated with higher risk of depression.7 _In _this

con-text,itisnoteworthytoconsiderthatnegativecorrelation waspresentbetweenanxietyscoresandeducationalstatus. Regarding these results, patients with higher educational levels seem to be compliant with medications. This may improvetheirwell-beingandresultinreducedanxiety.

It has been shown that effective treatment of the symptoms of rosacea leads signiﬁcant improvement of

psychosocialsymptomsandhealth-relatedQoL.17,19_In_fact,

anytreatmentstargetingblushinghelptoalleviate depres-sive symptoms and social anxiety.5 _Similarly, _the _present

studyfoundincreasedriskofanxietyinpatientswhohadnot beentreatedpreviously.Thesefindingscanbeexplainedby thefactthatofthe43untreatedpatients,81%attendedfor thefirsttime,whereastheremainingwerereturnpatients. Importantly,this study confirmed that female patients withrosaceaareparticularlyatriskofGAD.Itwasobserved that 84% (42/50)of these patientshad not been referred toapsychiatryclinicbefore.Detectionofhighnumbersof probable,previouslyundetectedGADcasesamongrosacea patientswasanotherinterestingfindingofthepresentstudy. Itmustberememberedthattheanxietytoolsusedinthis studyareunabletodetectcausality.Thereby,basedonthe resultsofthisstudy,itishardtoidentifywhetheranxiety couldbeadirectconsequenceofrosaceaoracoincidental finding.

Thelargesamplesizeandtheuseofvalidatedtoolsare the main strengthsof this study.However, this study has some limitations.The studypopulation maynotbe repre-sentativeofpatientsinthegeneralpopulation.Nonetheless, thishospitalprovidescaretoalargepercentageandawide rangeofsocio-economicclasseswhobelongtothe surround-ingcommunity.

Conclusion

These data suggest that rosacea patients appear tohave anxietyindependentoftheirdiseaseseverity.Somepatient groups maybeat greaterriskofhavinganxiety.Screening patientswithQoLtoolsmaynotreﬂectexact psychopathol-ogy.TheGAD-7andtheseveritymeasureoftheGAD-Adult arevalidandeasy-to-applytoolstodetectpatientsat risk indailyclinicalpractice.Physiciansshouldbeawareofthis relationshipinordertoprovidepsychologicalsupportaspart ofthepsychosomatictreatmentstrategy.

Ethical

approval

Writtenconsentwasobtainedfromallstudiedpatientsand controlsubjectsbeforethecollectionofdataand question-naires.The studyprotocolwasapprovedbytheUniversity of HealthSciences,Ankara NumuneTrainingandResearch Hospital EthicsCommitteeof ClinicalStudies (E-16-1064). ThestudyprotocolwasinaccordancewiththeHelsinki Dec-larationof1975.

Financial

support

Nonedeclared.

Author’s

contributions

Pınar Incel Uysal: Approval of the ﬁnal version of the manuscript;conceptionandplanningofthestudy; elabora-tionandwritingofthemanuscript;obtaining,analyzingand interpretingthedata;effectiveparticipationinresearch ori-entation;intellectualparticipationinpropaedeuticand/or

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therapeuticconductofthecasesstudied;criticalreviewof theliterature;criticalreviewofthemanuscript.

Neslihan Akdogan: Approvalof the ﬁnal version of the manuscript;obtaining,analyzingandinterpretingthedata; effectiveparticipationinresearchorientation;intellectual participationinpropaedeuticand/ortherapeuticconductof thecasesstudied;criticalreviewoftheliterature

Yildiz Hayran: Statistical analysis;approvalof theﬁnal version of themanuscript; elaboration and writing of the manuscript;effectiveparticipationinresearchorientation; intellectualparticipationinpropaedeuticand/or therapeu-tic conduct of the cases studied; critical review of the literature.

Ayse Oktem: Approval of the ﬁnal version of the manuscript;conceptionandplanningofthestudy; obtain-ing, analyzing and interpreting the data; effective par-ticipation in research orientation; critical review of the manuscript.

Basak Yalcin: Approval of the ﬁnal version of the manuscript;conceptionandplanningofthestudy;effective participation in research orientation; intellectual partici-pation inpropaedeuticand/or therapeutic conductof the casesstudied;criticalreviewofthemanuscript.

Conﬂicts

of

interest

Nonedeclared.

References

1.WilkinJ, DahlM,Detmar M, DrakeL, Feinstein A, OdomR, etal.Standardclassiﬁcationofrosacea:reportoftheNational RosaceaSociety ExpertCommittee onthe Classiﬁcation and StagingofRosacea.JAmAcadDermatol.2002;46:584---7. 2.GalloRL,GransteinRD,KangS,MannisM,SteinhoffM,TanJ,

etal.Standardclassiﬁcationandpathophysiologyofrosacea: the2017updatebytheNationalRosaceaSocietyExpert Com-mittee.JAmAcadDermatol.2018;78:148---55.

3.Gupta MA,Gupta AK, ChenSJ, Johnson AM. Comorbidity of rosaceaanddepression:ananalysisoftheNationalAmbulatory MedicalCareSurveyandNationalHospitalAmbulatoryCare Sur-vey---outpatientdepartmentdatacollectedbytheU.S.National CenterforHealthStatisticsfrom1995to2002.BrJDermatol. 2005;153:1176---81.

4.Abram K, Silm H, Maaroos HI, Oona M. Subjective dis-ease perception and symptoms of depression in relation to healthcare-seekingbehaviour in patients withrosacea. Acta DermVenereol.2009;89:488---91.

5.Su D, Drummond PD. Blushing propensity and psychologi-caldistress in peoplewith rosacea.ClinPsychol Psychother. 2012;19:488---95.

6.Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606---13.

7.Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Patients with rosacea have increased risk of depression and anxiety disorders: a Danish nationwide cohort study. Dermatology. 2016;232:208---13.

8.BewleyA,FowlerJ,SchöferH,KerroucheN,RivesV.Erythema ofrosaceaimpairshealth-related qualityoflife:resultsofa meta-analysis.DermatolTher(Heidelb).2016;6:237---47. 9.WuY,FuC,ZhangW,LiC,ZhangJ.Thedermatologylifequality

index(DLQI)andthehospitalanxietyanddepression(HADS)in Chineserosaceapatients.PsycholHealthMed.2018;23:369---74. 10.SpitzerRL,KroenkeK,WilliamsJB,LöweB.Abriefmeasurefor assessinggeneralizedanxietydisorder:theGAD-7.ArchIntern Med.2006;166:1092---7.

11.LöweB,DeckerO,MüllerS,BrählerE,SchellbergD,HerzogW, etal.ValidationandstandardizationoftheGeneralizedAnxiety DisorderScreener(GAD-7)inthegeneralpopulation.MedCare. 2008;46:266---74.

12.Psychiatry.org.Severitymeasureforgeneralizedanxiety disor-der--- adult;2013.Availablefrom:https://www.psychiatry.org/ psychiatrists/practice/dsm/educational-resources/assessment-measures[cited28.12.18].

13.Arck PC, Slominski A, Theoharides TC, Peters EM, Paus R. Neuroimmunologyofstress:skintakes centerstage.JInvest Dermatol.2006;126:1697---704.

14.CribierB.Theredface:art,historyand medical representa-tions.AnnDermatolVenereol.2011;138Suppl.3:S172---8. 15.Halioua B, Cribier B, Frey M, Tan J. Feelings of

stigmatiza-tioninpatientswithrosacea.JEurAcadDermatolVenereol. 2017;31:163---8.

16.Böhm D, Schwanitz P, Stock Gissendanner S, Schmid-Ott G, Schulz W. Symptom severity and psychological seque-lae in rosacea: results of a survey. Psychol Health Med. 2014;19:586---91.

17.MoustafaF,LewallenRS,FeldmanSR.Thepsychologicalimpact ofrosaceaandtheinﬂuenceofcurrentmanagementoptions.J AmAcadDermatol.2014;71:973---80.

18.Alinia H, Cardwell LA, Tuchayi SM, Nadkarni A, Bahrami N, Richardson IM, et al. Screening for depression in rosacea patients.Cutis.2018;102:36---8.

19.HeisigM,ReichA.Psychosocialaspectsofrosaceawithafocus on anxiety and depression. Clin Cosmet Investig Dermatol. 2018;11:103---7.

20.BeikertFC,LangenbruchAK,RadtkeMA,AugustinM.Willingness topayandqualityoflifeinpatientswithrosacea.JEurAcad DermatolVenereol.2013;27:734---8.