Prevalence of COVID-19 among patients with chronic inflammatory rheumatic diseases treated with biologic agents or small molecules: A population-based study in the first two months of COVID-19 outbreak in Italy

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Original

article

Prevalence

of

COVID-19

among

patients

with

chronic

inflammatory

rheumatic

diseases

treated

with

biologic

agents

or

small

molecules:

A

population-based

study

in

the

first

two

months

of

COVID-19

outbreak

in

Italy

Luca

Quartuccio

a,∗

_,

_Francesca

_Valent

b

_,

_Enrico

_Pasut

c

_,

_Carlo

_Tascini

d

_,

_Salvatore

_De

_Vita

a

a_{ClinicofRheumatology,DepartmentofMedicine(DAME),ASUFC,UniversityofUdine,Udine,Italy} b_{IgieneedEpidemiologiaClinica,ASUFC,Udine,Italy}

c_{ServiceofPharmacy,ASUFC,Udine,Italy} d_{InfectiousDiseasesUnit,ASUFC,Udine,Italy}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Accepted13May2020 Availableonlinexxx Keywords: Rheumatoidarthritis Rheumaticdisease Biologic Smallmolecule Tumornecrosisfactor Coronavirus COVID-19

a

b

s

t

r

a

c

t

Objective: Theaimofthisstudyistodeterminetheprevalenceofsevereacuterespiratorysyndrome coronavirus2(SARS-CoV-2)disease2019(COVID-19)amongadultpatientstreatedwithbiologicagents orsmallmoleculesforchronicinflammatoryrheumaticdiseases,inparticularforchronicinflammatory arthritides.

Methods: Tothisend,apopulation-basedstudy,intheprovinceofUdine(466,700inhabitants,with age>15yearsold,FriuliVeneziaGiuliaregion,Italy)wasplanned.Theprimaryoutcomewasthe preva-lenceofCOVID-19inthefirsttwomonthsoftheoutbreak.Alltherheumaticpatientstreatedwithbiologic agentsorsmallmoleculesinthelast6monthsinourprovincewereincluded(N=1051).

Results:FromFebruary29toApril25,2020,4adultpatients(4/1051,i.e.3.8/1000,95%ConfidenceInterval 1.5–9.7/1000)wereregisteredasswabtestpositivebyPCRforCOVID-19.Overall,atotalof47/1051(4.5%) casesweretestedforCOVID-19byPCRinthesameperiod,and15ofthemduetosymptomscompatible withCOVID-19.Inthegeneralpopulation,theprevalencewas937cases/466700(2/1000,95%Confidence Interval1.9–2.1/1000,P-value=0.33,chisquaretest),and20,179/466,700(4.3%)swabtestsforCOVID-19 wereperformed.

Conclusion:TheriskofCOVID-19inrheumaticpatientsunderbiologicagentsorsmallmoleculesdoes notappeardifferentfromthatobservedinthegeneralpopulation.Patientsshouldbeinformedtosafely proceedwiththeirtreatmentandfollowtherulesforself-protectiontoCOVID-19.

©2020Soci ´et ´efranc¸aisederhumatologie.PublishedbyElsevierMassonSAS.Thisisanopenaccess articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

The ongoing outbreak by novel coronavirus (COVID-19) has beendefinedasaglobalpublichealthemergencybyWorldHealth Organization(WHO)[1].COVID-19isaninfectiousdiseasecaused bysevereacuterespiratorysyndromecoronavirus2 (SARS-CoV-2)withdroplets and contact as themain way oftransmission. Currently,theresearchonCOVID-19is growingatgreat speed. Italyisoneofthecountryshowingthehighestrateofmortalityin theworld,mainlyinthenorthernregions[2].Whilepre-existing

∗ Corresponding author at: Clinicof Rheumatology,ASUFC, Department of Medicine(DAME),UniversityofUdine,Udine,Italy.

E-mailaddress:luca.quartuccio@asufc.sanita.fvg.it(L.Quartuccio).

pulmonaryandcardiovasculardiseaseaswellasdiabetesmellitus areknownriskfactorsfortheworstoutcomeforCOVID-19[3],the impactofchronicrheumaticdiseases,and,inparticular,iftherisk ofCOVID-19whileusingabiologicagent(b-DMARD)orasmall molecule(ts-DMARD)forchronicinflammatoryarthritisishigher thaninthegeneralpopulation,isstillunknown[1].Biologicagents increase therisk forinfections, althoughtheadvantageslargely overcomethat risk[4].Moreover,themostseverecomplication ofCOVID-19pneumoniaseemtobecausedbyacytokinestorm syndrome[5]asanexaggeratedresponseoftheimmunesystemto thevirus[4,6]forwhommanyrheumaticdrugs,includingbiologic agents,arecurrentlyunderinvestigations[7,8].

Prevalence data in patients with chronic inflammatory rheumatic diseases treated withb-DMARDs or ts-DMARDs and theirriskofCOVID-19arestillscarce,andlimitedtocaseseries

https://doi.org/10.1016/j.jbspin.2020.05.003

1297-319X/©2020 Soci ´et ´efranc¸aisederhumatologie. Publishedby ElsevierMassonSAS.This isan openaccessarticleundertheCC BY-NC-NDlicense(http://

[9–11].Thosepreliminarydatamaybereassuringforclinicians, but,importantly,theylackofcomparisontothereference popula-tion.Therefore,theaimofthisstudyistocomparetheprevalenceof COVID-19inthispopulationofpatientswiththegeneralpopulation inordertoprovideastrongerevidencesupportingthemanagement ofpatientswithinflammatoryrheumaticdiseasesduringCOVID-19 outbreak[12].

2. Methods

2.1. Objective

Theprimaryobjectiveofthepresentstudyistodefinethe preva-lenceand the severityofCOVID-19 in a populationofpatients sufferingfromachronicinflammatory rheumaticdiseaseunder treatmentwithabiologicagentorasmallmoleculeduringthefirst twomonthsofCOVID-19outbreak.

2.2. Studypopulationandreferencepopulation

Thecaseswerealltheadultpatientswitharheumaticdisease andwho wereundertreatmentwitha b-or ats-DMARDfrom September2019toApril2020intheprovinceofUdine,Italy.A computerdatabasefromthePharmacyserviceoftheprovinceof Udinerecordingpastandpresenttreatmentswithb/ts-DMARDsin thesamecaseswasused.Alltheclinicalchartsofthesecaseswere revisedtoverifytheywereproceedingwithtreatmentatthelast contact.TheprevalenceofCOVID-19duringthemonthofMarch 2020andApril2020wascomparedtothatofthegeneral popu-lationintheprovinceofUdineafterexcludingsubjects≤15years old(atotalof466,700inhabitants),thefirstCOVID-19caseinthis provincebeingreportedonFebruary29,2020.Importantly,inour region,allthepatientswhoundergoabiologicorsmallmolecule treatmentmustbeevaluatedbyapublicconsultant rheumatolo-gisteverysixmonthsforrenewingandproceedingwiththeirown therapeuticplanandthentheyneedtoberegisteredbythe Phar-macyservicethatsuppliesthedrugabouteverytwomonthsuntil tothetreatmentplanexpiration.

2.3. ProceduretomakediagnosisofCOVID-19

DiagnostictestsforCOVID-19wereconductedin accordance withtheindicationprovidedbytheItalianMinistryofHealth, fol-lowingtherulessuggestedbytheWHO,insymptomaticsubjects. ForinitialdiagnostictestingforCOVID-19,theItalianMinistryof Healthrecommendscollectingandtesting anupperrespiratory specimen.Anasopharyngealspecimenisthepreferredchoicefor swab-basedCOVID-19testing.Allthepeopleoftheprovinceof Udine,and inparticular,alltherheumaticpatientstreatedwith b/ts-DMARDS,aswellasotherpatientstreatedwith immunosup-pressiveorcytotoxicagentsforotherdiseases,wereinformedby nationalandlocalmediatocontacttheirowngeneralpractitioner (GP)incaseofsymptomssuchasbodytemperatureover37.4◦C, cough,ordyspnoea.Inturn,theGPsentthepatientstoundergo testingforCOVID-19,wheneverthisinfectionwassuspected.

Routineidentification of cases of COVID-19 is based onthe detectionofuniquesequencesofvirusRNAbynucleicacid ampli-ficationtests(NAAT)suchasRT-PCRwithconfirmationbynucleic acidsequencing.Thefollowinggenesareinvestigated:Egenefor screeningandthenRdRpandNgenesofSARS-CoV-2for confirma-tion.WHOprovidedaninterimguidancetolaboratoriesshowing thestrategicuseofdiagnostictestingindifferenttransmission sce-nariosoftheCOVID-19outbreak,includinghowtojustifytesting whenhavingtoprioritizepatientsduetolackofproperfacilities. TheWHOdocumentspecifiestheconditionsnecessarytoconsider

acaselaboratory-confirmedbyNAATforareaswithnoknownor establishedCOVID-19circulation[13].

2.4. Statisticalmethods

Variableswereexpressedasmean±standarddeviationor fre-quency, as appropriate. Comparison between study population andgeneralreferencepopulationwasperformedbyChi2 _test.

P-value<0.05wasconsideredsignificant.Thestudywasconductedin accordancewiththeethicalprinciplesoftheHelsinkiDeclaration, andapprovedbythelocalEthicsCommittee(CEUR-2020-Os-129).

3. Results

3.1. Epidemiologydata

Within theprovince of Udine, 1053patientstaking biologic drugsorsmallmoleculeswereidentified.Ofthem,twopatients wereexcludedsincetheysuspendedthedrugafteradiagnosisof cancer.Theywere703(66.9%)womenand348(33.1%)men,with ameanageof58.4±14.6years.

FromFebruary29(firstcaseofCOVID-19infectionreportedin theprovinceofUdine)toApril25,2020,atotalof47/1051cases weretestedforCOVID-19(4.5%):15/47(31.9%)becauseof symp-toms,and20/47(42.5%)sincetheywerehealthcareproviderswith apreviouscontactwithaprovenCOVID-19positivesubject,and 11/47(23.4%)forwardtriagerules.Thus,15/1051(1.4%)patients underwentCOVID-19swabtestbecauseofsymptoms.

Fourcases(4/1051,i.e.3.8/1000,95%ConfidenceInterval 1.5-9.7/1000)wereprovedtobetest positivetoCOVID-19,noneof themamongthehealthcareproviders.Detaileddescriptionofthem isreportedintablesfrom1to3.Inthereferencegeneral popu-lation,onApril25,2020,theprevalencewas937cases/466,700 (2/1000,95%ConfidenceInterval1.9-2.1/1000,P-value=0.33,chi squaretest).Screeningswabtestswereperformedin20,179 sub-jectsinageneralpopulationofabout466,700inhabitants(4.3%).

Inordertoprovidebackgroundinformationonourstudy popu-lation,completedataontheunderlyingrheumaticdiseasewere available for 925/1051 (88%). The diagnoseswere: rheumatoid arthritis(362,39.1%),psoriaticarthritis(275,26.7%),ankylosing spondylitisornon-radiographicspondyloarthritis(176,19.0%), sys-temicvasculitides(74,8.0%),systemic lupuserythematosus(38, 4.1%),otherchronicinflammatorydiseases(19,2.1%).Overall,549 (59.3%)patientsweretakinganti-TNFagent(inparticular adali-mumab,202,21.8%,oretanercept,210,22.7%),90(9.7%)patients weretakingananti-IL6receptorantibody,67(9.6%)patientswere takingananti-IL17oranti-IL12/23agent,73(6.9%)weretaking aJAKinhibitor.Theothertreatmentswereabatacept(48,4.8%), rituximab(38,4.1%),belimumab(29,3.1%),anakinra (13,1.4%), canakinumab(1,0.1%),apremilast(2,0.2%).Comorbiditieswere hypertensionin277(29.9%),type2diabetesin65(7.0%),heart dis-easein109(11.8%).Sevenhundredandfifty-eightofthesepatients (81.9%) had been under biologic treatment for more than one year,and393patients(42.5%)formorethan5years.Concomitant therapywithglucocorticoids(meandosageatthelastfollow-up visit4.7±3.9mg/dayofprednisoneequivalent)wasusedby146 patients(15.8%),andatraditionalsyntheticDMARD,wasusedby 355patients(38.4%),mainlymethotrexate(257/355,i.e.72.4%of them).Antimalarialswereemployedby72patients(7.8%). 3.2. Caseseriesdescription

Table1

Demographicandclinicalcharacteristicsofthefourpatients.

Feature Pt.1 Pt.2 Pt.3 Pt.4

Sex Female Male Female Male

Age 42 69 68 62

Rheumaticdiseaseas indicationforthe biologicagent

Non-radiographicSpA andsuppurative hydradenitis

AS RA AS

Ongoingb/ts-DMARD ADA40/weekly GOL50mgmonthly TOF5mgtwicedaily GOL50mgmonthly

Exposuretothelast b/ts-DMARD(months)

12 72 4 38

Exposureto b/ts-DMARDs

From2019 From2006 From2012 From2017

Previoustreatments None MTX,LEFETA,ADA, LEF,CYC,ETA,ADA,

ABA,TCZ,CZP,BARI

None Otherconcomitant

DMARD

None MTX15mg/weekly MTX10mg/weekly None

Glucocorticoids (prednisone equivalent/day)

No Yes(5mg/day) Yes(5mg/day) No

Otherongoing treatments Isoniazide, budesonide/formoterol fumaratedihydrate Bisoprolol,furosemide, kanrenol,digoxin,apixaban, duloxetine,

oxycodone/naloxone, lansoprazole,folicacid

Valsartan/hydrochlorothiazide, fentanyl,folicacid

None

Smoking Yes,currently No No Yes,currently

Obesity No Yes No No

Comorbidity Renalangiomyolipoma, latentTB(stillunder isoniazid),asthma

Chronicheartfailure;chronic atrialfibrillation,aorticvalve insufficiency,milddilatationof theascendingaorta;chronic bronchitis;fibromyalgia Systemicarterial hypertension, complicated osteoporosiswith vertebralfractures LatentTB(previously treatedwithisoniazid for9months)

Influenzavaccination Yes Yes Yes Yes

SpA:spondyloarthritis;AS:ankylosingspondylitis;RA:rheumatoidarthritis;b/ts-DMARD,biologic/targetedsyntheticdiseasemodifyingdrug;ADA,adalimumab;GOL: golimumab;ETA:etanercept;CZP,certolizumabpegol;ABA,abatacept;TCZ,tocilizumab;BARI,baricitinib;TOF:tafacitinib;MTX,methotrexate,LEF,leflunomide;CYC, cyclosporine;TB,tuberculosis.

Table2

CharacteristicsofCovid-19infectioninthefourpatients.

Pt.1 Pt.2 Pt.3 Pt.4

Swabtestpositive,date March,03 March,26 March,13 March,21

RiskfactorsforCOVID-19 Yes,recentholidayin NorthwesternItaly

Notknown Notknown Notknown

COVID-19manifestations Fever Fatigue,dyspnoea,intense oraldryness

Fever,dyspnoea,fatigue, nausea

Fever

COVID-19severity Mild High Moderate Mild

Hospitalization Yes Yes Yes No

Oxygensupport No Yes Yes No

Mechanicalventilation No No No No

AdmissiontoICU No No No No

TreatmentforCOVID-19 Lopinavir/Ritonavir, ribavirin

Lopinavir/Ritonavir Lopinavir/Ritonavir, hydroxychloroquine

None

Lungimaging RXnegative RXandCTscanpositivefor

pneumonia

RXpositiveforpneumonia No

Recovery Yes(dischargeafterone

day)

Yes(dischargeafter10 days)

Yes(dischargeafter11 days)

Yes

Swabre-test Negativeafter10days Negativeafter7days Negativeafter27days Negativeafter25days

moleculesalongtheclinicalhistoryofthosepatientsrangedfrom 12to72months.Otherconcomitanttreatmentsfortherheumatic diseaseincludingmethotrexateandlow-doseofprednisoneintwo ofthem.Threeoutoffourpresentedpre-existingcomorbidities includingactivepulmonaryorcardiovasculardiseases.

3.3. Viralinfection

CharacteristicsoftheCOVID-19infectionarereportedinTable2. Briefly,threepatientsrequiredhospitaladmissionandtwoofthem neededoxygensupport,butnonewassubsequentlytransferredto ICU.Allbutoneofthepatientsreceivedantiviraldrugsandone alsohydroxychloroquine.Allpatientsshowedafavorableoutcome.

Laboratory features of the three hospitalized patients were reportedinTable3.

4. Discussion

Table3

Laboratorydataathospitaladmission.

Pt.1 Pt.2 Pt.3

Hemoglobin(g/dl) 13.7 12.5 8.4

WhiteBloodcellcount(cell/mcl) 11040 4870 6390

Neutrophils(cell/mcl) 6100 3720 5600 Lymphocyte(cell/mcl) 2140 470 370 Platelets(cell/mcl) 437000 230000 345000 C-ReactiveProtein(mg/l) 4.17 88.5 92.1 Procalcitonin(ng/ml) <0.01 0.14 0.03 Creatinine(mg/dl) 0.56 1.00 0.89

Electrolytes Normal Hyponatriemia,128mMol/l Hyponatriemia,129mMol/l

AST/ALT(IU/l) Normal Normal Normal

CK(IU/l) 74 193 449

LDH(IU/l) 272 470 278

BNP(pg/ml) Notavailable 213 Notavailable

TroponinI(ng/ml) Notavailable Negative Negative

D-dimer(ng/ml) Notavailable 488 Notavailable

Ferritin(ng/ml) Notavailable Notavailable 40

AST:aspartatetransaminase;ALT:alaninetransaminase;CK:creatinekinase;LDH:lactatedehydrogenase;BNP:b-typenatriureticpeptide. prevalenceofCOVID-19withthatobservedinthereferencegeneral

populationofadultsinthesameprovince.TheCOVID-19prevalence of3.8/1000(95%ConfidenceInterval1.5–9.7/1000)reportedbyus isnotdifferentfromthatestimatedinthereferencegeneral popu-lation.Onthecontrary,itisknownthatb-DMARDsandts-DMARDs putpatientsatsignificantlyhigherriskofinfections[6],especially intherespiratorytract,thanthegeneralpopulation.Therefore,our resultis reassuringforclinicians,and,thus,b-orts-DMARDsin rheumaticdiseasescouldneithersubstantiallyincreasetheriskof COVID-19,norworsenthecourseofCOVID-19,whenitoccurs.This observationisconsistentwithpreviousfindingsduringthe previ-ousoutbreaks,suchasSARSandMiddleEastrespiratorysyndrome, regardingfavorable outcomeinimmunosuppressed patientsfor organtransplantation,cancerorautoimmunediseases[14–16].

Even if the true rate of COVID-19 is not known either in thegeneralpopulationoramong rheumaticpatients,rheumatic patientsunderimmunosuppressorsareusuallymorepronetoalert cliniciansinthecaseofsymptomsofinfection,andtoprotect them-selvesearlier frompossiblecontagion.The number of patients, whowere tested forCOVID-19 (4.5%) wassimilartothe refer-encepopulation(4.3%).However,amongrheumaticpatientstested forCOVID-19,onlyonethird(15/47,31.9%)referredtohealthcare providersforsymptomscompatiblewithCOVID-19,thus under-lyingapossiblesocialbehaviorofpatientswithrheumaticdisease (i.e.,beingmorecarefulinsocialcontactsbecauseoftheir immuno-suppression)thatlikelyplayedanimportantroleininfectionrate andcontrol.Thisfeatureneedsappropriatestudies.Overall,itisan importantobservation,thoughitneedstobeconfirmedbyother groups,since this is a largepopulationofchronic immunosup-pressedpatients,and,amongthedifferentsubgroupsofrheumatic patients,theyprobablyrepresentthoseathighestriskfor infec-tiouscomplicationsbothfortheirownclinicalcharacteristics(age, comorbidity,moderatetosevereinflammatorychronicrheumatic disease)andrelatedtreatments(chronicglucocorticosteroids, b-orts-DMARD,longdiseaseduration,combinationoftwo immuno-suppressors),asalreadyknown[17].Welimitedouranalysisto rheumatic diseases that required biologic treatments or small molecules,thusthemajorityofpatientswithchronicinflammatory arthritisnotrequiringthosetreatments,aswellasthemajorityof patientswithrarerautoimmunesystemicdiseases,likesystemic lupuserythematosusorsystemicvasculitides,werenotincluded. Anyway, among patients suffering from chronic inflammatory arthritides,thosetakingbiologicsareatgreaterinfectiousriskthan theothers.PreviousepidemiologicdataalsoinourregionofItaly supportedthisnotion[18].Thepossiblemitigationofsymptomsby biologicagentsorsmallmoleculescannotbeexcluded,thuscausing anunderestimationofCOVID-19inourstudypopulation.Finally,

theweightofantimalarialsinpossiblydecreasingtheprevalenceof COVID-19inourstudypopulationwasnegligible(<10%).However, antimalarialsfailedtoreducemortalityincriticallyillCOVID-19 patientsinarecentrandomizedcontrolledtrial[19],andfurther studiesarewarranted[20].

Yet,more than 50% of our patientshave been in treatment withananti-TNFagent(adalimumabandetanercept,inparticular), therefore,ourconclusionsaremoreproperlyapplicableinpatients withchronicinflammatoryarthritideswhoaretakingananti-TNF agent.

Finally,regardingourfourpatientspositiveforCOVID-19,the infectiousdiseasewasgenerallycharacterizedbyafavorable out-come,inlinewiththerecentlyreportedcaseseries[9–11].

Toconclude,theriskofCOVID-19inchronically immunosup-pressed rheumatic patientsunder biologics or small molecules doesnot appearhigherthanthegeneralpopulation,in particu-larforthosepatientswithchronicinflammatoryarthritidestaking ananti-TNFagent.Overall,theoutcomeoftheinfectionmightbe favorable.Thus,patientsshouldbeinformedtosafelyproceedwith theirtreatmentsduringtheoutbreak,andtostrictlyadheretothe principlesforself-protectiontoCOVID-19.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

Contributions

LQdesigneddatacollectiontools,monitoreddatacollectionfor thewholestudy,wrotethestatisticalanalysisplan,cleanedand analysedthedata,anddraftedandrevisedthepaper.Heis guar-antor.FVandSDVimplementedthestatisticalanalysis,analysed thedata,draftedandrevisedthepaper.EP,CTanalysedthedata, draftedandrevisedthepaper.

Funding

Thisresearchreceivednoexternalfunding.

Ethicalapprovalinformation

Datasharingstatement

Thedatathatsupportthefindingsofthisstudyareavailableon requestfromthecorrespondingauthor,[LQ].

Acknowledgements

GinevraDeMarchi,MD,StefaniaSacco,MD,AlenZabotti,MD, ElenaTreppo,MD,GermanaModesti,MPH,RobertoAgarinis,MD, GiuliaDelFrateMDcontributedtothiswork.

Localpatients’associationsforrheumaticdiseasesandgeneral practitionerswereinvolvedintheidentifyingthistopicasanurgent needforthebestmanagementofimmunosuppressivetreatments, andinparticularbiologicagentsorsmallmolecules,inthis out-break.

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