SARS-CoV-2 outbreak in immune-mediated inflammatory diseases: the Euro-COVIMID multicentre cross-sectional study

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 A icles e482 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. A icles www. helance .com/ heuma ology Vol 3 July 2021 e483 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 A icles e484 www. helance .com/ heuma ology Vol 3 July 2021 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 A icles www. helance .com/ heuma ology Vol 3 July 2021 e485 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 A icles e486 www. helance .com/ heuma ology Vol 3 July 2021 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 A icles www. helance .com/ heuma ology Vol 3 July 2021 e487 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 A icles e488 www. helance .com/ heuma ology Vol 3 July 2021 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 . 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