www. helance .com/ heuma ology Vol 3 July 2021
e481
A icles
Lance Rheuma ol 2021;
3: e481–88
Published Online
Ap il 28, 2021
h ps://doi.o g/10.1016/
S2665-9913(21)00112-0
See Commen page e462
Dépa emen de Médecine
In e ne e Immunologie
Clinique, G oupe Hospi alie
Pi ié-Salpê iè e, So bonne
Uni e si é, Assis ance
Publique–Hôpi aux de Pa is
(AP-HP), Pa is, F ance
(P o D Saadoun PhD,
M Viei a MD, M Vau ie MD,
P o P Cacoub MSc); Cen e
Na ional de Ré é ences
Maladies Au oimmunes
Sys émiques Ra es, Cen e
Na ional de Ré é ences
Maladies Au oin lamma oi es
e Amylose In lamma oi e,
In lamma ion-
Immunopa hology-Bio he apy
Depa men , Inse m 959,
G oupe Hospi alie Pi ié-
Salpê iè e, AP-HP, Pa is,
F ance (P o D Saadoun,
M Viei a, M Vau ie ,
P o P Cacoub);
Rheumazen um Ruh gebie
He ne, Ruh -Uni e si y
Bochum, Bochum, Ge many
(
P o X Ba aliakos PhD,
I And eica MD);
Rheuma ology
Depa men , Cen o Hospi ala
e Uni e si á io de Coimb a,
Coimb a, Po ugal
(
P o J A P da Sil a PhD,
M Sousa MD, M Luis MD);
Ins i u e o Clinical and
Biomedical Resea ch, Facul y o
Medicine, Uni e si y o
Coimb a, Po ugal
(
P o J A P da Sil a);
Rheuma ology Depa men ,
Hospi al de San a Ma ia—
Cen o Hospi ala Uni e si á io
Lisboa No e, Cen o
Académico de Medicina de
Lisboa, Lisbon, Po ugal
(
N Khmelinskii MD)
;
Rheuma ology Resea ch Uni ,
Ins i u o de Medicina
Molecula , Faculdade de
SARS-CoV-2 ou b eak in immune-media ed in lamma o y
diseases: he Eu o-COVIMID mul icen e c oss-sec ional
s udy
Da id Saadoun, Ma heus Viei a, Ma hieu Vau ie , Xeno on Ba aliakos, Ioana And eica, José A P da Sil a, Ma lene Sousa, Ma iana Luis,
Niki a Khmelinskii, José Ma ía Al a o G acía, Isabel Cas ejon, Juan Ca los Nie o Gonzalez, Ca lo Albe o Sci è, E o e Sil agni,
Alessand a Bo oluzzi, Hen y Penn, Shahi Hamdulay, Ped o M Machado, B uno Fau el, Pa ice Cacoub, Ma hieu Resche-Rigon, Lau e Gossec
Summa y
Backg ound The COVID-19 pandemic has aised nume ous ques ions among pa ien s wi h immune-media ed
in lamma o y diseases ega ding po en ial ecip ocal e ec s o COVID-19 and hei unde lying disease, and po en ial
e ec s o immunomodula o y he apy on ou comes ela ed o COVID-19. The se op e alence o SARS-CoV-2 and
ac o s associa ed wi h symp oma ic COVID-19 in pa ien s wi h immune-media ed in lamma o y diseases a e s ill
unclea . The Eu o-COVIMID s udy aimed o de e mine he se ological and clinical p e alence o COVID-19 among
pa ien s wi h immune-media ed in lamma o y diseases, as well as ac o s associa ed wi h COVID-19 occu ence and
he impac o he pandemic in i s managemen .
Me hods In his mul icen e c oss-sec ional s udy, pa ien s aged 18 yea s o olde wi h a clinical diagnosis o
heuma oid a h i is, axial spondyloa h i is, sys emic lupus e y hema osus, Sjög en’s synd ome, o gian cell a e i is
we e ec ui ed om six e ia y e e al cen es in F ance, Ge many, I aly, Po ugal, Spain, and he UK. Demog aphics,
como bidi ies, ea men s, and ecen disease la es, as well as in o ma ion on COVID-19 symp oms, we e collec ed
h ough a ques ionnai e comple ed by pa icipan s. SARS-CoV-2 se ology was sys ema ically es ed. The main
ou come was he se ological and clinical p e alence o COVID-19. Fac o s associa ed wi h symp oma ic COVID-19
we e assessed by mul i a iable logis ic eg ession, and incidence o ecen disease la es, changes in ea men s o
unde lying disease, and he easons o ea men changes we e also assessed. This s udy is egis e ed wi h
ClinicalT ials.go , NCT04397237.
Findings Be ween June 7 and Dec 8, 2020, 3136 pa ien s wi h an immune-media ed in lamma o y disease answe ed
he ques ionnai e. 3028 pa ien s (median age 58 yea s [IQR 46–67]; 2239 [73·9%] women and 789 [26·1%] men) wi h
symp oma ic COVID-19, se ological da a, o bo h we e included in analyses. SARS-CoV-2 an ibodies we e de ec ed
in 166 (5·5% [95% CI 4·7–6·4]) o 3018 pa ien s who had se ology es s. Symp oma ic COVID-19 occu ed in 122 (4·0%
[95% CI 3·4–4·8]) o 3028 pa ien s, o whom 24 (19·7%) we e admi ed o hospi al and ou (3·3%) died. Fac o s
associa ed wi h symp oma ic COVID-19 we e highe concen a ions o C- eac i e p o ein (odds a io 1·18, 95% CI
1·05–1·33; p=0·0063), and highe numbe s o ecen disease la es (1·27, 1·02–1·58; p=0·030), whe eas use o
biological he apy was associa ed wi h educed isk (0·51, 0·32–0·82; p=0·0057). A leas one disease la e occu ed
in 654 (21·6%) o 3028 pa ien s. O e he s udy pe iod, 519 (20·6%) o 2514 pa ien s had ea men changes, o which
125 (24·1%) we e due o he pandemic.
In e p e a ion This s udy p o ides key insigh s in o he epidemiology and isk ac o s o COVID-19 among pa ien s
wi h immune-media ed in lamma o y diseases. O e all, immunosupp essan s do no seem o be dele e ious in his
scena io, and he con ol o in lamma o y ac i i y seems o be key when acing he pandemic.
Funding P ize , Sano i, Amgen, Galapagos, and Lilly.
Copy igh © 2021 Else ie L d. All igh s ese ed.
In oduc ion
Despi e he onse o he COVID-19 pandemic in Eu ope
by Ma ch, 2020, no la ge-scale na ionwide Eu opean
se op e alence s udies ha e been published so a , excep
in Spain, whe e he p e alence o an ibodies agains
SARS-CoV-2 in he gene al popula ion was only 5% by
May, 2020.1 The bu den o COVID-19 has been epo ed o
be highe in speci ic a - isk popula ions, including people
wi h ch onic condi ions such as diabe es and
ca dio ascula disease. Many conce ns ha e been aised
ega ding COVID-19 in pa ien s wi h immune-media ed
in lamma o y diseases, which a ec an es ima ed 4·5% o
he global popula ion.2 Pa ien s wi h immune-media ed
in lamma o y diseases a e known o be a highe isk o
se e e in ec ions, no only due o hei baseline immune
dys unc ion bu also as a consequence o immuno-
supp essan he apy. Pooled da a om se en case-con ol
s udies es ima ed he isk o symp oma ic COVID-19 in
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www. helance .com/ heuma ology Vol 3 July 2021
Medicina, Uni e sidade de
Lisboa, Lisbon, Po ugal
(N Khmelinskii); Rheuma ology,
Hospi al Gene al Uni e si a io
G ego io Ma añón, Mad id,
Spain (P o J M A G acía MD,
P o I Cas ejon PhD,
J C N Gonzalez PhD);
Rheuma ology Uni ,
Depa men o Medical
Sciences, Uni e si y o Fe a a,
Fe a a, I aly (P o C A Sci è PhD,
E Sil agni MD, A Bo oluzzi PhD);
Epidemiology Uni , I alian
Socie y o Rheuma ology,
Milan, I aly (
P o C A Sci è);
Depa men o Rheuma ology,
London No h Wes Uni e si y
Heal hca e NHS T us London
No h Wes Uni e si y
Heal hca e NHS T us , London,
UK (
H Penn MD,
S Hamdulay PhD,
P o P M Machado PhD);
Cen e
o Rheuma ology and
Depa men o Neu omuscula
Diseases, Uni e si y College
London, London, UK
(
P o P M Machado);
So bonne
Uni e si é,
Pie e Louis
Ins i u e o Epidemiology and
Public Heal h, Inse m
UMR 1136, Pa is, F ance
(P o B Fau el PhD,
P o L Gossec PhD); APHP,
So bonne Uni e si é,
Rheuma ology Depa men ,
Pi ié-Salpê iè e Hospi al,
Pa is, F ance (
P o B Fau el,
P o L Gossec); Cen e Na ional
de Ré é ences Maladies
Au oin lamma oi es e
Amylose In lamma oi e, FAI
2
R
Ne wo k, Pa is, F ance
(P o B Fau el); URC Sain -
Louis, AP-HP, Hôpi al Sain -
Louis, Pa is, F ance
(P o M Resche-Rigon PhD)
Co espondence o:
P o Da id Saadoun,
Dépa emen de Médecine
In e ne e d’Immunologie
Clinique, G oupe Hôpi al Pi ié-
Salpê iè e, So bonne Uni e si é,
AP-HP, 75013 Pa is, F ance
[email p o ec ed]
pa ien s wi h an immune-media ed in lamma o y disease
a wo imes highe han ha in he gene al popula ion.3
Se e al ac o s migh a ec he isk and disease se e i y in
his he e ogeneous g oup o pa ien s. I was pos ula ed
ha he se e i y o COVID-19 would inc ease wi h highe
deg ees o immuno sup p ession, as use o a combina ion
o immuno supp essan s has been associa ed wi h highe
isk o hospi al admission and dea h due o COVID-19.3
Con e sely, conside ing he immune-media ed mech-
anisms unde lying se e e COVID-19,4 in lamma ion-
dampening ea men s migh ac ually con e p o ec ion
agains se e e COVID-19 o some pa ien s.
Ano he consequence o COVID-19 in pa ien s wi h
immune-media ed in lamma o y diseases is he sub-
s an ial isk o un imely discon inua ion o immuno modu-
la ing agen s by hemsel es o hei ea ing physicians
due o ea ha hese agen s could p edispose hem o
COVID-19, despi e eassu ing in e na ional guidelines.5,6
The e ec o COVID-19 on he con ol o disease, including
a possible isk o la es, in hese pa ien s is ano he key
ques ion. The e has been a pauci y o da a add essing
hese issues, and whe he disease ac i i y, immuno-
modula o y he apy, o bo h migh ha e an e ec on
COVID-19 emains unclea .
The Eu o-COVIMID s udy was designed o assess he
se op e alence o SARS-CoV-2 in pa ien s in Eu ope wi h
immune-media ed in lamma o y diseases, and he e ec
o COVID-19 on he unde lying disease. Ou main goal
was o p o ide a mo e eliable es ima e o he exposu e o
SARS-CoV-2 in his popula ion.
Me hods
S udy design and pa icipan s
We did a mul icen e c oss-sec ional s udy (Eu o-
COVIMID) o pa ien s ollowed up in six e ia y e e al
cen es in Île-de-F ance (F ance), No d hein-Wes alen
(Ge many), Emilia Romagna (I aly), Cen o (Po ugal),
Comunidad de Mad id (Spain), and London (UK). Eligible
indi iduals had o be olde han 18 yea s and ha e a
de ini e clinical diagnosis o heuma oid a h i is, axial
spondyloa h i is, sys emic lupus e y hema osus,
Sjög en’s synd ome, o gian cell a e i is diagnosed by
expe ienced heuma ologis s and ul illing he espec i e
in e na ional classi ica ion c i e ia.7–11 Pa ien s who
e used o pa icipa e, did no speak o ead he local
language, o we e unwilling o unde go ou ine blood
collec ion du ing he s udy pe iod we e excluded.
The s udy p o ocol was implemen ed acco ding o he
Decla a ion o Helsinki and was app o ed by he
Ins i u ional Re iew Boa d om each cen e. Pa ien s
ag eed o pa icipa e h ough ei he in o med o al o
w i en consen based on he equi emen s o each local
e hics commi ee. A pa ien pa ne (G on K ause, based
in Pa is, F ance) was in ol ed in he s udy design and in
Resea ch in con ex
E idence be o e his s udy
Since he beginning o he COVID-19 pandemic,
many conce ns ha e been aised ega ding he isks o
COVID-19 in pa ien s wi h immune-media ed in lamma o y
diseases. Pa ien s wi h hese diseases a e known o be a
highe isk o se e e in ec ions, no only due o hei baseline
immune dys unc ion bu also as a consequence o
immunosupp essan he apy. He e ogeneous pooled da a
ha e es ima ed ha he isk o COVID-19 in pa ien s wi h
immune-media ed in lamma o y diseases is highe han in
he gene al popula ion and ha immunosupp essan s migh
be associa ed wi h an inc eased isk o dea h due o
COVID-19. Howe e , hese da a we e om s udies in which
SARS-CoV-2 se ology es ing was no done, meaning ha
mild and asymp oma ic cases we e likely o be missed,
and esul ing in an unde es ima ion o he p e alence o
COVID-19 and an o e es ima ion o i s se e i y. We sea ched
PubMed, Embase, ScienceDi ec , and Google Schola o
pee - e iewed English-language epidemiological s udies
published up o Feb 1, 2021, using he e ms “se op e alence”,
“se ology”, “SARS-CoV-2”, “COVID-19”, “immune-media ed
disease”, “au oimmune disease”, “ heuma oid a h i is”,
“axial spondyloa h i is”, “sys emic lupus e y hema ous”,
“Sjög en’s synd ome”, and “gian cell a e i is”. La ge-scale
se op e alence s udies in pa ien s wi h immune-media ed
in lamma o y diseases ha e no been done so a .
Added alue o his s udy
We de e mined he p e alence o COVID-19 among 3028 pa ien s
wi h immune-media ed in lamma o y diseases ( heuma oid
a h i is, axial spondyloa h i is, sys emic lupus e y hema osus,
Sjög en’s synd ome, and gian cell a e i is) ac oss six Eu opean
coun ies using a sys ema ic se ological assessmen . We ound
ha he o e all se op e alence and se e i y o SARS-CoV-2
in ec ion in hese pa ien s o e he s udy pe iod esembled ha o
he gene al popula ion. In addi ion, inc eased sys emic
in lamma ion in pa ien s wi h immune-media ed in lamma o y
diseases (highe C- eac i e p o ein concen a ions and a highe
numbe o disease la es) was associa ed wi h symp oma ic
COVID-19. Symp oma ic SARS-CoV-2 in ec ion occu ed less
equen ly among pa ien s wi h immune-media ed in lamma o y
diseases ea ed wi h biological d ugs.
Implica ions o all he a ailable e idence
An unde s anding o he ue p e alence o COVID-19 in
pa ien s wi h immune-media ed in lamma o y diseases and
eliable isk s a i ica ion could be use ul in he design o
p io i isa ion s a egies when ca ying ou mass accina ion.
Immunosupp essan s do no seem o be dele e ious wi h ega d
o suscep ibili y o and se e i y o COVID-19, and he con ol o
in lamma o y ac i i y could be a p ima y goal in he
managemen o pa ien s wi h immune-media ed in lamma o y
disease du ing he pandemic.
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he de elopmen o he pa ien ques ionnai e, ollowing
he ules p oposed by he Eu opean League Agains
Rheuma ism and Ou come Measu es in Rheuma ology
Clinical T ials.12,13 Pa ien s and he public we e no
in ol ed in conduc ing, epo ing, o in he dissemina ion
plans o his esea ch.
Da a collec ion and de ini ions
Du ing 7 mon hs o he pandemic in Eu ope ( om
June o Decembe , 2020), consecu i e pa ien s wi h an
immune-media ed in lamma o y disease ollowed up in
he ou pa ien clinic o h ough phone consul a ions
we e in i ed o pa icipa e. Pa ien s who ag eed we e
in e iewed by heal h p o essionals, who illed in a
cen alised and anonymised elec onic case epo o m,
which included pa ien s’ demog aphic in o ma ion,
como bidi ies, clinical his o y, and numbe o disease
la es ( om Feb 1, 2020, un il he da e o inclusion). The
case epo o m also included da a on cu en use o
immunosupp essan and immunomodula o y d ugs
du ing he same pe iod, along wi h dose changes and
he easons o hese changes ( ela ed o no o he
pandemic). S able measu es (ie, no majo changes om
p e ious alues) o C- eac i e p o ein a ailable om he
pas 24 weeks we e eco ded.
In o ma ion ega ding con ac wi h someone known o
be in ec ed wi h SARS-CoV-2, compliance o qua an ine,
and clinical cou se we e eco ded, as well as he onse and
du a ion o COVID-19 symp oms. In he e en o dea h,
he da e and cause o dea h we e e ie ed om medical
eco ds and amily membe s. Fo all li ing pa ien s,
se ological es s o SARS-CoV-2 we e added o hei
ou ine blood collec ion wi hin 4 weeks o illing in he
case epo o m. These es s could be done ei he a he
e ia y cen e o a he pa ien ’s usual ex e nal labo a o y,
p o ided ha one o he ollowing high-accu acy es s
we e used: Abbo ’s IgG es (Abbo Pa k, IL, USA), which
de ec s he SARS-CoV-2 nucleocapsid p o ein; Roche’s
o al an ibody es (Basel, Swi ze land), which de ec s he
SARS-CoV-2 nucleocapsid p o ein; Siemens’ o al an ibody
es (New Yo k, NY, USA), which de ec s he SARS-CoV-2
spike p o ein S1 ecep o -binding domain; DiaSo in’s IgG
es (Saluggia, I aly), which de ec s he SARS-CoV-2 spike
p o ein S1 o S2; o Beckman-Coul e ’s IgG es (B ea, CA,
USA), which de ec s he SARS-CoV-2 spike p o ein S1
ecep o -binding domain.
The numbe o la es we e assessed, and hei se e i y
was de ined acco ding o he equi emen o ea men
changes o hospi al admission as ollows: e y mild, i no
medical a en ion was sough and no ea men
in ensi ica ion was needed; mild, i medical a en ion was
sough and no o sligh ea men in ensi ica ion was
needed; mode a e, i a hospi al s ay in a medical wa d
was equi ed; and se e e, i in ensi e ca e ea men was
equi ed. A COVID-19 diagnosis was conside ed as
con i med i ypical cli nical symp oms we e accompanied
by ei he a posi i e SARS-CoV-2 PCR o se ological es .
COVID-19 se e i y was ca ego ised using he WHO
o dinal scale o clinical imp o emen .14 This scale akes
in o accoun he wo s clinical s a us and he highes le el
o suppo needed h oughou he disease cou se as
ollows: (1) ambula o y, no limi a ion o ac i i ies;
(2) ambula o y, wi h limi a ion o ac i i ies; (3) hospi alised,
no oxygen he apy; (4) hospi alised, oxygen by mask o
nasal p ongs; (5) hospi alised, oxygen by non-in asi e
en ila ion o high- low oxygen; (6) in uba ion and
mechanical en ila ion; (7) mechanical en ila ion wi h
addi ional o gan suppo (ie, asop esso s, dialysis, o
ex a co po eal memb ane oxygena ion); (8) dea h.
Ou comes
The main ou come was he se ological and clinical
p e alence o COVID-19 in a la ge sample o pa ien s
wi h immune-media ed in lamma o y diseases in
Eu ope. Seconda y ou comes included he assessmen o
COVID-19 se e i y, ac o s associa ed wi h COVID-19
occu ence, incidence and se e i y o ecen la es o he
unde lying disease, and changes in ea men s and he
easons unde lying hese changes.
S a is ical analysis
Assuming a p e alence o SARS-CoV-2 an ibodies o 5%,15
a sample size o 323 p oduces an exac wo-sided 95% CI
o 0·05. Thus, we aimed o ec ui 100 pa ien s pe
coun y and pe disease o ensu e a su icien p ecision in
he es ima ions (ie, a o al o a leas 3000 pa ien s).
We included all pa ien s wi h a ailable se ological
o clinical COVID-19 da a in analyses. Se ological and
clinical COVID-19 p e alence was es ima ed wi h wo-
sided 95% CIs. We also compu ed p e alence es ima es
acco ding o coun ies and unde lying disease. To
compa e he p e alence o symp oma ic COVID-19 in
pa ien s wi h immune-media ed in lamma o y diseases
wi h ha o he gene al popula ion, we es ima ed he
p e alence o COVID-19 cases o each egion h oughou
he ec ui men pe iod by aking alues om he UK and
Eu opean dashboa ds16,17 and using hose o calcula e
numbe o cases pe 100 inhabi an s.
Con inuous a iables a e p esen ed as medians wi h
IQRs and we e compa ed be ween g oups using he
Wilcoxon ank-sum es . Ca ego ical a iables a e
p esen ed wi h coun s and pe cen ages and we e
compa ed using χ² es s wi h con inui y co ec ion o
Fishe exac es s as app op ia e. We used mul iple
logis ic eg essions wi h a andom e ec on he coun y
o de e mine a se o a iables independen ly associa ed
wi h symp oma ic COVID-19. All ac o s signi ican ly
associa ed wi h symp oma ic COVID-19 we e conside ed
in he eg ession model. A backwa d p ocedu e wi h a
s opping ule on p alues o less han 0·05 was applied.
Odds a ios (ORs) wi h wo-sided 95% CIs we e
es ima ed. We did sensi i i y analyses o check he
consis ency o esul s using a gene alised linea model
wi h penalised maximum likelihood, and o assess he
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e ec o missing da a using mul iple impu a ion by
chained equa ion. All es s we e wo-sided, and a p alue
below 0·05 was conside ed as signi ican . Analyses we e
done wi h R s a is ical pla o m so wa e ( e sion 4.0.3).
This s udy is egis e ed wi h ClinicalT ials.go ,
NCT04397237.
Role o he unding sou ce
The unde o he s udy had no ole in he s udy design,
da a collec ion, da a analysis, da a in e p e a ion, w i ing
o he epo , o in he decision o submi he pape o
publica ion.
Resul s
Be ween June 7 and Dec 8, 2020, 3136 pa ien s wi h
an immune-media ed in lamma o y disease comple ed
he ques ionnai e ( igu e 1). O hese pa ien s,
3028 (96·6%) had a ailable COVID-19 da a, se ological
da a, o bo h (median age 58 yea s [IQR 46–67];
2239 [73·9%] women and 789 [26·1%] men; able 1).
En olmen a e was cons an h oughou he s udy pe iod.
Median du a ion o immune-media ed in lam ma o y
disease was 8·7 yea s (IQR 3·3–17·4) a en olmen , and
median C- eac i e p o ein concen a ion was 3·0 mg/L
(2·0–4·5; able 1). One o mo e como bidi ies we e
obse ed in 1624 (53·6%) o 3028 pa ien s and included
mainly hype ension (899 [29·7%] o 3028), dyslipidaemia
(411 [13·6%]), obesi y (245 [8·1%]), dep ession (218 [7·2%]),
diabe es (200 [6·6%]), and cance his o y (196 [6·5%];
appendix p2). 1303 (48·2%) o 2076 pa ien s ecei ed an
in luenza accine in 2019, and 946 (36·0%) o 2629 pa ien s
ecei ed a pneumococcal accine in he pas 5 yea s.
992 (32·8%) pa ien s we e aking p ednisone (median daily
dose 5 mg [IQR 3–6]), wi h 1645 (54·3%) ecei ing a leas
one con en ional syn he ic disease-modi ying an i heu-
ma ic d ug (DMARD) and 1086 (35·9%) ecei ing a leas
one biological DMARD ( able 1; appendix pp 3–5).
O he 3028 included pa ien s, all bu en had
a se ological es ( able 2), and he mos used es ki s
we e hose om Abbo (1293 [48·4%] o 2674; da a
missing o 344 pa ien s) and Roche (302 [11·3%]). A
posi i e se ology esul was ound in 166 pa ien s (5·5%
[95% CI 4·7–6·4]). Di e ences we e obse ed among
coun ies, wi h a lowe p opo ion o se oposi i e
pa ien s in Ge many (5 [0·8%] o 624), Po ugal (6 [1·1%]
o 526), and I aly (8 [1·5%] o 522) han in F ance
(42 [7·1%] o 593), Spain (70 [13·4%] o 524), and he UK
(35 [14·6%] o 239; appendix pp 6–8). The cha ac e is ics
o pa ien s wi h immune-media ed in lam ma o y
diseases acco ding o SARS-CoV-2 se ology a e de ailed
in he appendix (pp 9–14). In pa ien s wi h de ec able
SARS-CoV-2 an ibodies, C- eac i e p o ein concen-
a ions we e highe and he p opo ion o cu en
smoke s was lowe . No signi ican di e ences we e
obse ed be ween se oposi i e and se o nega i e pa ien s
wi h ega d o pa ien demog aphics, como bidi ies, and
medica ions o unde lying disease.
The p e alence o symp oma ic COVID-19 among
he 3028 pa ien s was 4·0% (95% CI 3·4–4·8); speci ic
symp oms a e de ailed in he appendix (p 1). Symp oma ic
COVID-19 occu ed in 122 pa ien s (112 wi h se ology
da a [92 posi i e, 20 nega i e], en wi hou se ology da a);
24 (19·7%) equi ed hospi al admission and ou (3·3%)
died ( able 2). Asymp oma ic in ec ion was no ed in 74
(44·6%) o 166 people wi h de ec able an ibodies agains
SARS-CoV-2. The occu ence o symp oma ic COVID-19
was associa ed wi h highe C- eac i e p o ein concen-
a ions (p=0·038), median daily dose o p ednisone
(p=0·0058), and numbe o disease la es (p=0·0018), bu
lowe use o biological DMARDs (p=0·0009) and lowe
p e alence o cu en smoking (p=0·0085; able 1). No
di e ences we e obse ed in he occu ence o symp o-
ma ic COVID-19 wi h espec o age and como bidi ies
( able 1; appendix p 2).
All ac o s signi ican ly associa ed wi h symp oma ic
COVID-19 in he uni a ia e analysis we e conside ed in
he mul i a iable logis ic eg ession model. The ac-
o s associa ed wi h he occu ence o symp oma ic
COVID-19 in mul i a ia e analysis we e highe le els o
C- eac i e p o ein (OR o each 10 mg/L inc emen 1·18
[95% CI 1·05–1·33], p=0·0063) and highe numbe o
ecen disease la es (OR o each addi ional la e 1·27
[1·02–1·58], p=0·030). By con as , use o biological o
a ge ed syn he ic DMARDs was associa ed wi h a
educed occu ence o symp oma ic COVID-19 (OR 0·51
[95% CI 0·32–0·82], p=0·0057; igu e 2).
The p e alence o symp oma ic COVID-19 based on
he Eu o-COVIMID da a was highe han he epo ed
local p e alence in he UK, whe eas p e alence based on
he Eu o-COVIMID da a was lowe han he epo ed
local p e alence in all o he coun ies (appendix p 15).
A leas one disease la e was epo ed by 654 (21·6%)
o 3028 pa ien s, o which 309 (47·2%) we e e y mild,
303 (46·3%) we e mild, 40 (6·1%) we e mode a e, and
Figu e 1: COVID-19 p e alence in he Eu o-COVIMID s udy popula ion
IMID=immune-media ed in lamma o y disease.
3018 had se ological es s
166 we e posi i e o
SARS-CoV-2
3136 pa ien s wi h an IMID
comple ed he ques ionnai e
3028 included in analyses
108 excluded due o no
COVID-19 and se ology
da a
122 had symp oma ic COVID-19
(de e mined by PCR o
se ological es s)
94 ou pa ien s
24 admi ed o hospi al
4 died
See Online o appendix
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All pa ien s*
(n=3028)
Pa ien s wi h symp oma ic
COVID-19 (n=122)
Pa ien s wi h asymp oma ic o
no COVID-19 (n=2906)
p alue
Age, yea s 58 (46–67) 58 (48–68) 58 (46–67) 0·67
18–29 141 (4·7%) 6 (4·9%) 135 (4·6%) ··
30–39 286 (9·4%) 11 (9·0%) 275 (9·5%) ··
40–49 501 (16·5%) 18 (14·8%) 483 (16·6%) ··
50–59 764 (25·2%) 32 (26·2%) 732 (25·2%) ··
60–69 706 (23·3%) 31 (25·4%) 675 (23·2%) ··
≥70 630 (20·8%) 24 (19·7%) 606 (20·9%) ··
Sex ·· ·· ·· 1·00
Female 2239 (73·9%) 90 (73·8%) 2149 (74·0%) ··
Male 789 (26·1%) 32 (26·2%) 757 (26·0%) ··
Body-mass index, kg/m² 24·98 (22·04–28·28) 24·23 (22·21–28·16) 24·98 (22·04–28·28) 1·00
Smoking ·· ·· ·· 0·0085
Cu en 483/2587 (18·7%) 9/95 (9·5%) 474/2492 (19·0%) ··
Fo me 705/2587 (27·3%) 37/95 (38·9%) 668/2492 (26·8%) ··
Ne e 1399/2587 (54·1%) 49/95 (51·6%) 1350/2492 (54·2%) ··
A leas one como bidi y 1624 (53·6%) 66 (54·1%) 1558 (53·6%) 0·99
Posi i e SARS-CoV-2 se ology* 166 (5·5%) 92/112 (82·1%) 74 (2·5%) <0·0001
IMID ·· ·· ·· 0·50
Rheuma oid a h i is 891 (29·4%) 39 (32·0%) 852 (29·3%) ··
Axial spondyla h i is 670 (22·1%) 19 (15·6%) 651 (22·4%) ··
Sys emic lupus e y hema ous 605 (20·0%) 28 (23·0%) 577 (19·9%) ··
Sjög en’s synd ome 511 (16·9%) 21 (17·2%) 490 (16·9%) ··
Gian cell a e i is 351 (11·6%) 15 (12·3%) 336 (11·6%) ··
Disease du a ion, yea s 8·7 (3·3–17·4) 8·4 (3·4–15·7) 8·6 (3·3–17·3) 0·99
C- eac i e p o ein, mg/L† 3·0
(2·0–4·5; n=2520)
3·0
(3·0–6·4; n=96)
3·0
(2·0–4·4; n=2424)
0·038
Numbe o IMID la es ·· ·· ·· 0·0018
None 2374 (78·4%) 82 (67·2%) 2292 (78·9%) ··
One 516 (17·0%) 27 (22·1%) 489 (16·8%) ··
Two 75 (2·5%) 9 (7·4%) 66 (2·3%) ··
Th ee 32 (1·1%) 2 (1·6%) 30 (1·0%) ··
Fou o mo e 31 (1·0%) 2 (1·6%) 29 (1·0%) ··
Se e i y o IMID la es ·· ·· ·· 0·73
Ve y mild 309/654 (47·2%) 19/40 (47·5%) 290/614 (47·2%) ··
Mild 303/654 (46·3%) 17/40 (42·5%) 286/614 (46·6%) ··
Mode a e 40/654 (6·1%) 4/40 (10·0%) 36/614 (5·9%) ··
Se e e 2/654 (0·3%) 0 2/614 (0·3%) ··
IMID ea men s ·· ·· ·· ··
No ea men 379 (12·5%) 17 (13·9%) 362 (12·4%) 0·73
Non-s e oidal an i-in lamma o y
d ugs
362 (12·0%) 12 (9·8%) 350 (12·0%) 0·55
P ednisone 992 (32·8%) 44 (36·1%) 948 (32·6%) 0·49
Daily dose, mg 5 (3–6; n=987) 5 (5–8; n=44) 5 (3–6; n=943) 0·0058
A leas one con en ional syn he ic
DMARD
1645 (54·3%) 73 (59·8%) 1572 (54·1%) 0·25
A leas one biological o a ge ed
syn he ic DMARD
1086 (35·9%) 26 (21·3%) 1060 (36·5%) 0·0009
Da a a e median (IQR), n (%), o n/N (%) unless o he wise speci ied. Pe cen ages migh no sum o 100% due o ounding. DMARD=disease-modi ying an i heuma ic d ug.
IMID=immune-media ed in lamma o y disease. *Se ology es esul was no a ailable o en symp oma ic pa ien s wi h COVID-19. †Las s able biological pa ame e s e e
o he 24 weeks be o e inclusion.
Table 1: Cha ac e is ics o all pa ien s wi h immune-media ed in lamma o y diseases and acco ding o he p esence o COVID-19 symp oms

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wo (0·3%) we e se e e ( able 2). 519 (20·6%) o
2514 pa ien s had changes in hei ea men
be ween June and Decembe , 2020. The eason o he
changes was he pandemic in 125 (24·1%) pa ien s
( able 3). Co ico s e oids we e he mos equen ly
changed d ug du ing he pandemic (219 [22·1%] o
992 pa ien s), and mo e han hal o he apeu ic changes
we e a educ ion o cessa ion o ea men a he han
an inc ease in ea men .
Discussion
In his mul icen e c oss-sec ional s udy, we de e mined
o he i s ime ( o ou knowledge) he p e alence o
COVID-19 among pa ien s wi h immune-media ed
in lamma o y diseases ac oss six Eu opean coun ies by
using a sys ema ic se ological assessmen . The o e all
se op e alence and e ec s o SARS-CoV-2 in pa ien s
wi h immune-media ed in lamma o y diseases o e he
s udy pe iod esembles ha o he gene al popula ion.
Inc eased sys emic in lamma ion (ie, highe C- eac i e
p o ein concen a ions and disease la es) migh play a
pa in he occu ence o symp oma ic COVID-19,
whe eas biological and a ge ed syn he ic DMARDs
appea ed o be p o ec i e. Mo e han 20% o pa ien s
included in analyses had a leas one disease la e.
A sys ema ic se ological assessmen is he bes way o
achie e a b oad unde s anding o dis inc popula ions.
Da a om China showed a SARS-CoV-2 se oposi i i y
a e anging om 3·2% o 3·8% be ween Ma ch and
Ap il, 2020,18 and in he la ges na ionwide popula ion-
based s udy so a in Spain, se op e alence eached 5% by
May, 2020.1 Repea ed c oss-sec ional analysis ac oss all
US ju isdic ions ha e shown ha less han 10% o he
popula ion had de ec able SARS-CoV-2 an ibodies as o
Sep embe , 2020.19 The se op e alence is expec ed o
inc ease as we app oach a - isk popula ions, bu hese
da a a e s ill sca ce o se e al g oups o pa ien s. Fo
pa ien s on dialysis in he USA, a la ge na ionwide
analysis es ima ed p e alence o SARS-CoV-2 an ibodies
o be 8% by July, 2020.20 We es ima ed a se op e alence o
5·5% in pa ien s wi h immune-media ed in lamma o y
diseases o e he 6-mon h s udy pe iod. In addi ion, as
has been epo ed in he gene al popula ion, we ound
di e ences be ween COVID-19 p e alence ac oss
Eu opean coun ies. This inding migh e lec he di -
e en deg ees o es ic i e measu es applied in each
egion. We could hypo hesise ha pa ien s wi h immune-
media ed in lamma o y diseases om ou e ia y cen es
we e mo e adhe en o physical dis ancing measu es, as
Figu e 2: Fo es plo o he odds o symp oma ic COVID-19
The OR o C- eac i e p o ein co esponds o a pe 10 mg/L inc ease in concen a ion, and o numbe o la es i
co esponds o each addi ional la e. DMARDs=biological disease-modi ying an i heuma ic d ugs. OR=odds a io.
C- eac i e p o ein
Biological o a ge ed syn he ic DMARDs
Numbe o la es
1·18 (1·05–1·33)
0·51 (0·32–0·82)
1·27 (1·02–1·58)
0·0063
0·0057
0·030
p alueOR (95% CI)
0·25 0·50 0·75 1·00 1·25 1·50 1·75
Pa ien s
T ea men changes du ing he pandemic
(June–Decembe , 2020)
519/2514 (20·6%)
Due o he pandemic 125/519 (24·1%)
No ela ed o he pandemic 394/519 (75·9%)
Change in co icos e oids 219/992 (22·1%)
Dose inc ease 102/219 (46·6%)
Dose dec ease 90/219 (41·1%)
In e up ion 27/219 (12·3%)
Change in con en ional syn he ic DMARDs 199/1645 (12·1%)
Dose inc ease 83/199 (41·7%)
Dose dec ease 46/199 (23·1%)
In e up ion 70/199 (35·2%)
Change in biological o a ge ed syn he ic
DMARDs
193/1086 (17·8%)
Dose inc ease 40/193 (20·7%)
Dose dec ease 72/193 (37·3%)
In e up ion 81/193 (42·0%)
Da a a e n/N (%). 379 pa ien s ecei ed no ea men , and da a on ea men
changes we e una ailable o 135 pa ien s. DMARDs=disease-modi ying
an i heuma ic d ugs.
Table 3: E ec o he COVID-19 pandemic on ea men s o immune-
media ed in lamma o y diseases
Pa ien s (n=3028)
SARS-CoV-2 se ology*
Posi i e esul 166/3018 (5·5%)
Posi i e IgA 3/3018 (0·1%)
Posi i e IgM 11/3018 (0·4%)
Posi i e IgG 122/3018 (4·0%)
To al an ibodies posi i i y 39/3018 (1·3%)
Symp oma ic COVID-19 122 (4·0%)
Close con ac wi h a con i med COVID-19 case 54/122 (44·3%)
Non-adhe ence o con inemen 24/122 (19·7%)
Heal h p o essional 9/24 (37·5%)
Symp om du a ion, days 10 (7–20)
WHO o dinal scale o clinical imp o emen
No limi a ions o ac i i ies 65/122 (53·3%)
Limi a ion o ac i i ies, home oxygen, o bo h 29/122 (23·8%)
Hospi alisa ion wi hou supplemen al oxygen 4/122 (3·3%)
Hospi alisa ion wi h low- low oxygen 18/122 (14·8%)
Non-in asi e en ila ion o high- low oxygen 1/122 (0·8%)
Mechanical en ila ion 1/122 (0·8%)
Mechanical en ila ion and addi ional o gan
suppo
0
Dea h 4/122 (3·3%)
Da a a e n/N (%) o median (IQR). *Se ology es esul was no a ailable o
en symp oma ic pa ien s wi h COVID-19.
Table 2: In o ma ion on SARS-CoV-2 se ology and symp oma ic
COVID-19 o pa ien s wi h immune-media ed in lamma o y diseases
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pa ien s om Ge many, I aly, and Po ugal had signi i-
can ly less con ac wi h people wi h con i med COVID-19
han did hose om he o he s udied coun ies.
The COVID-19 epidemiology in pa ien s wi h immune-
media ed in lamma o y diseases has se e al biases ha
make he da a di icul o in e p e . Among he inhe en
selec ion biases om case se ies, o e es ima ing disease
se e i y is he mos ele an one. In he la ges wo ldwide
case se ies o pa ien s wi h heuma ic diseases om
he COVID-19 Global Rheuma ology Alliance egis y,
49% o pa ien s we e admi ed o hos pi al and 10·5% died.21
Ou s udy showed com pa a i ely lowe a es o hospi al
admission (19·7%) and dea hs (3·3%) among pa ien s
wi h symp oma ic COVID-19, which a e close o hose o
he gene al popula ion.22 Se e al s udies ha e assessed
la ge ixed samples;23–25 howe e , he sca ci y o sys ema ic
se ological es ing does no allow o he de ec ion o mild
and asymp oma ic in ec ions and hus unde mines
p e alence calcula ions. Ou inding ha 44·6% o
pa ien s wi h immune-media ed in lamma o y diseases
who had posi i e SARS-CoV-2 se ology had asymp oma ic
in ec ion makes he p e alence and se e i y o COVID-19
ound in his popula ion mo e eliable.
The mechanisms unde lying he de elopmen o
symp o ma ic COVID-19 emain unclea . Olde age and
como bidi ies ha e been highligh ed as key poo p og-
nosis ac o s o COVID-19 in he gene al popula ion,26,27
and hese associa ions ha e also been sugges ed o
pa ien s wi h immune-media ed in lamma o y diseases.3,21
Howe e , hese indings we e no ep oduced in ou s udy.
No ably, highe C- eac i e p o ein concen a ions and
numbe o disease la es accoun ed o he main isk
ac o s o symp oma ic COVID-19. Highe disease ac i i y
a COVID-19 diagnosis has been associa ed wi h dea h
among pa ien s wi h immune-media ed in lamma o y
diseases in a la ge case se ies.21 Taken oge he , hese
indings sugges ha he in lam ma o y s a us migh play
a pa in he de elopmen o COVID-19 and i s ou comes.
One o he mos ele an issues in COVID-19 isk o
pa ien s wi h immune-media ed in lamma o y diseases
conce ns he use o immunosupp essan s, ei he because
o he highe implici isk o in ec ions o because se e al
DMARDs (eg, ocilizumab and ba ici inib) ha e been
p oposed as ea men s o se e e o ms o COVID-19.
Highe doses o co icos e oid and DMARD combina ion
he apy we e associa ed wi h a highe mo ali y isk due o
COVID-19 among pa ien s wi h immune-media ed
in lamma o y diseases.3,21 By con as , a la ge e ospec i e
su ey showed ha pa ien s aking hyd oxychlo oquine
p esen ed a educed isk o COVID-1923 (al hough o he
s udies ha e no con i med his) and ea ly da a om he
COVID-19 Global Rheuma ology Alliance showed an
associa ion be ween he use o umou nec osis ac o
inhibi o s and educed odds o hospi alisa ion.28 S ikingly,
use o biological o a ge ed syn he ic DMARDs educed
he isk o symp oma ic COVID-19 by almos 50% in ou
s udy. Ra he han a speci ic biological DMARD, he
con ol o he o e all in lamma o y esponse seems o be
key in whe he a pa ien de elops symp oma ic COVID-19.
Managemen o pa ien s wi h immune-media ed
in lam ma o y diseases has been a ec ed by he pandemic.
Remo e consul a ions inc eased as he numbe o ace- o-
ace consul a ions dec eased by up o 52%.29 T ea men
decisions we e equen ly pos poned, and specialis s
we e less likely o s a pa ien s on biological DMARDs
du ing he pandemic.30 Despi e he ecommenda ions
o he Eu opean League Agains Rheuma ism and he
Ame ican College o Rheuma ology,5,6 mo e han 20% o
pa icipan s in ou s udy wi h immune-media ed
in lamma o y diseases educed o discon inued hei
ea men du ing he s udy pe iod, he pandemic being
he eason in 24·1% o cases. In his se ing, a leas one
disease la e was seen in 21·6% o pa ien s. As guidelines
o managemen o immune-media ed in lamma o y
diseases du ing he pandemic a e p esen ed as li ing
documen s, ou da a a e use ul no only in ea i ming
he sa e y o main aining DMARDs, bu also in es ima ing
he a e o la es and hei se e i y du ing he ou b eak.
Ou s udy has limi a ions. As we do no ha e pa ien -
le el da a ega ding sociodemog aphic da a such as
employmen s a us, income, and household size, we
could no weigh hese componen s in he COVID-19 isk.
Addi ionally, by en olling a single e ia y e e al cen e
pe coun y, included pa ien s migh no ully ep esen
he gene al popula ion o pa ien s wi h immune-media ed
in lamma o y diseases in each egion.
In conclusion, his s udy p o ides key insigh s in o he
epidemiology and isk ac o s o COVID-19 among
pa ien s wi h immune-media ed in lamma o y diseases.
These da a will help o imp o e he managemen o
COVID-19 in his pa ien popula ion, pa icula ly a he
ime when accina ion s a egies s a o be widely
implemen ed.
Con ibu o s
DS, MVi, MVa, MR-R and LG concep ualised he s udy. MVi, DS, MVa,
XB, IA, JAPdS, MS, ML, NK, JMAG, IC, JCNG, CAS, ES, AB, HP, SH,
PMM, BF, PC, and LG we e in ol ed in da a collec ion and analysis.
MR-R did he s a is ical analysis. MVi, DS, and MR-R e i ied he
unde lying da a. MVi and DS w o e he ini ial d a o he manusc ip .
All au ho s c i ically con ibu ed o he a icle and app o ed he
submi ed e sion. DS had he inal esponsibili y o he decision o
submi o publica ion.
Decla a ion o in e es s
DS has ecei ed g an o esea ch suppo om Amgen, Galapagos,
Sano i, Janssen, Lilly, P ize , Roche Chugai, Mylan, GlaxoSmi hKline,
and Hi ibio, and consul ing ees om AbbVie, Amgen, Janssen,
Celgene, Sano i, and UCB ou side he submi ed wo k. ES has ecei ed
esea ch suppo om AbbVie ou side he submi ed wo k. LG has
ecei ed g an o esea ch suppo om Amgen, Lilly, Janssen, P ize ,
Sandoz, Sano i, and Galapagos, and consul ing ees om AbbVie,
Amgen, B is ol Mye s Squibb, Biogen, Celgene, Gilead, Janssen, Lilly,
No a is, P ize , Samsung Bioepis, Sano i-A en is, and UCB ou side he
submi ed wo k. PMM has ecei ed consul ing o speake ’s ees om
AbbVie, B is ol Mye s Squibb, Celgene, Eli Lilly, Janssen, Me ck Sha p &
Dohme, No a is, O phazyme, P ize , Roche, and UCB ou side he
submi ed wo k, and is suppo ed by he UK Na ional Ins i u e o
Heal h Resea ch and Uni e si y College London Hospi als Biomedical
Resea ch Cen e. XB has ecei ed g an o esea ch suppo om AbbVie
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and No a is, and consul ing ees om AbbVie, Amgen, B is ol Mye s
Squibb, Celgene, Cell ion, Galapagos, Gilead, Janssen, Lilly, No a is,
P ize , and UCB ou side he submi ed wo k. JMAG is pa ially
suppo ed by he Ins i u o de Salud Ca los III. All o he au ho s decla e
no compe ing in e es s.
Da a sha ing
Da a a e a ailable on easonable eques o he co esponding au ho .
Acknowledgmen s
P ize , Sano i, Amgen, Galapagos, and Lilly unded his s udy h ough
un es ic ed g an s. We hank all pa ien s and all physicians in ol ed in
he ca e o he pa ien s and ha helped in da a collec ion. The p omo e
and sponso o he s udy was he G oupe d’É udes e de Reche che su la
Pa hologie de l’Appa eil Locomo eu , a no - o -p o i , hospi al-based
esea ch associa ion om Pa is, F ance. We hank specially Amine
Ghembaza, Gaëlle Le oux, Geo gina Maalou , and Gonçalo Bole o
(Dépa emen de Médecine In e ne e Immunologie Clinique,
G oupe Hospi alie Pi ié-Salpê iè e, So bonne Uni e si é, Assis ance
Publique–Hôpi aux de Pa is (AP-HP), Pa is, F ance), and Violaine Fol z
(So bonne Uni e si é, Pie e Louis Ins i u e o Epidemiology and Public
Heal h, Inse m UMR 1136, Pa is, F ance)
o pa ien ec ui men in
Pa is, F ance. We also hank Clai e Ha is, F ianne Cawa,
Jai a Mukhe jee, Kal ee Flo a, Rhys Haywa d, and Ziad Fa ah
(Cen e o Rheuma ology and Depa men o Neu omuscula Diseases,
Uni e si y College London, London, UK) o hei con ibu ion o he
s udy in he UK, namely pa ien ec ui men and assessmen . We hank
Gab ielle on K ause as he pa ien pa ne o he s udy.
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