Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment : routine care data from 13 registries in the EuroSpA collaboration

O iginal esea ch D ug e en ion, inac i e disease and esponse a es in 1860 pa ien s wi h axial spondyloa h i is ini ia ing secukinumab ea men : ou ine ca e da a om 13 egis ies in he Eu oSpA collabo a ion B igi e Michelsen , 1,2,3 Ul Linds öm , 4 Ca alin Cod eanu, 5 Ad ian Ciu ea , 6 Jakub Za ada, 7 Anne Gi e Lo , 8,9 Manuel Pombo-Sua ez, 10 Fa os Onen, 11 To e K K ien , 3 Ziga Ro a , 12 Ma ia Jose San os , 13 Flo enzo Iannone, 14 Anna- Ma i Hokkanen, 15 Bjo n Gudbjo nsson, 16 Johan Askling, 17 Ruxand a Ionescu, 5 Michael J Nissen, 18 Ka el Pa elka, 19 Ca los Sanchez-Pied a, 20 Se e Aka , 21 Joseph Sex on, 3 Ma ija Tomsic, 12 Helena San os, 22 Ma co Sebas iani, 23 Jenny Ös e lund, 15 A ni Jon Gei sson, 24 Ga y Mac a lane, 25 I ene an de Ho s - B uinsma, 26 S ylianos Geo giadis, 1 Cecilie Heegaa d B ahe , 1 Lykke Mid bøll Ø nbje g, 1 Me e e Lund He land, 1,27 Mikkel Øs e gaa d 1,27 ABSTRACT Objec i es To explo e 6-mon h and 12-mon h secukinumab e ec i eness in pa ien s wi h axial spondyloa h i is (axSpA) o e all, as well as ac oss (1) numbe o p e ious biologic/ a ge ed syn he ic disease- modi ying an i heuma ic d ugs (b/ sDMARDs), (2) ime since diagnosis and (3) di e en Eu opean egis ies. Me hods Real-li e da a om 13 Eu opean egis ies pa icipa ing in he Eu opean Spondyloa h i is Resea ch Collabo a ion Ne wo k we e pooled. Kaplan-Meie wi h log- ank es , Cox eg ession, χ² and logis ic eg ession analyses we e pe o med o assess 6-mon h and 12-mon h secukinumab e en ion, inac i e disease/low-disease-ac i i y s a es (Ba h Ankylosing Spondyli is Disease Ac i i y Index (BASDAI) <2/<4, Ankylosing Spondyli is Disease Ac i i y Sco e (ASDAS) <1.3/<2.1) and esponse a es (BASDAI50, Assessmen o Spondyloa h i is In e na ional Socie y (ASAS) 20/40, ASDAS clinically impo an imp o emen (ASDAS-CII) and ASDAS majo imp o emen (ASDAS-MI)). Resul s We included 1860 pa ien s ini ia ing secukinumab as pa o ou ine ca e. O e all 6-mon h/12-mon h secukinumab e en ion a es we e 82%/72%, wi h signi ican (p<0.001) di e ences be ween he egis ies (6-mon h: 70–93%, 12-mon h: 53–86%) and ac oss numbe o p e ious b/ sDMARDs (b/ sDMARD-naï e: 90%/ 84%, 1 p io b/ sDMARD: 83%/73%, ≥2 p io b/ sDMARDs: 78%/66%). O e all 6-mon h/12-mon h BASDAI<4 we e obse ed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% o he pa ien s. All a es di e ed signi ican ly ac oss numbe o p e ious b/ sDMARDs, we e nume ically highe o b/ sDMARD-naï e pa ien s and a ied signi ican ly ac oss egis ies. O e all, ime since diagnosis was no associa ed wi h secukinumab e ec i eness. Conclusions In his s udy o 1860 pa ien s om 13 Eu opean coun ies, we p esen he i s comp ehensi e eal-li e da a on e ec i eness o secukinumab in pa ien s To ci e: Michelsen B, Linds öm U, Cod eanu C, e al.D ug e en ion, inac i e disease and esponse a es in 1860 pa ien s wi h axial spondyloa h i is ini ia ing secukinumab ea men : ou ine ca e da a om 13 egis ies in he Eu oSpA collabo a ion. RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020- 001280 ►Supplemen al ma e ial is published online only. To iew please isi he jou nal online (h p://dx.doi.o g/10.1136/ mdo pen-2020-001280). MLH and MØ con ibu ed equally Recei ed 20 Ap il 2020 Re ised 2 July 2020 Accep ed 21 Augus 2020 © Au ho (s) (o hei employe (s)) 2020. Re-use pe mi ed unde CC BY-NC. No comme cial e-use. See igh s and pe missions. Published by BMJ. Fo numbe ed a ilia ions see end o a icle. Co espondence o B igi e Michelsen; b igi e. michelsen@ egionh.dk Key messages Wha is al eady known abou his subjec ? ►Secukinumab has in RCTs shown e icacy in he ea men o axSpA, bu obse a ional s udies con i ming hese indings a e lacking. Wha does his s udy add? ►Secukinumab e en ion, inac i e disease, low- disease-ac i i y and esponse a es di e ed signi ican ly ac oss numbe o p e ious b/ sDMARDs, wi h o e all be e ou comes wi h less p e ious use o b/ sDMARDs, whe eas ime since diagnosis had no signi ican impac on ou comes. ►The o e all 6- and 12-mon h secukinumab e en ion was high and compa able o s udies on TNFi. ►Response a es we e lowe han in RCTs, bu pos - ea men disease s a es and esponse a es we e compa able o s udies on TNFi. How migh his impac on clinical p ac ice? ►The s udy suppo s he e ec i eness o secukinumab in he ea men o axSpA, bu also unde lines he need o head- o-head s udies on ea men e ec i eness o TNFi and IL-17 pa hway inhibi o s. Spondyloa h i is Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 1 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om wi h axSpA. O e all, secukinumab e en ion a es a e 6 and 12 mon hs o ea men we e high. Secukinumab e ec i eness was consis en ly be e o bionaï e pa ien s, independen o ime since diagnosis and di e ed ac oss he Eu opean coun ies. INTRODUCTION Axial spondyloa h i is (axSpA) is a ch onic, in lamma- o y, heuma ic disease cha ac e ised by in lamma ion and damage in he sac oiliac join s and spine, causing in lamma o y back pain, disabili y and impai ed quali y o li e. 12 In pa ien s wi h pe sis en ly high disease ac i i y despi e con en ional ea men , biologic disease- modi ying an i heuma ic d ugs (bDMARDs) a e used, mos o en umou nec osis ac o inhibi o s (TNFi). 3 In 2015, he new-mode-o -ac ion d ug secukinumab was app o ed by he Eu opean Medicines Agency o use in ankylosing spondyli is. This ully human IgG1 monoclo- nal an ibody a ge ing in e leukin-17A 4 has shown signi - ican e icacy in he ea men o axSpA in andomised con olled ials (RCTs). 5–7 Acco ding o cu en Assess- men o Spondyloa h i is In e na ional Socie y (ASAS)- EULAR ecommenda ions, secukinumab is ecom- mended a e ailu e o he i s TNFi. 3 The e is o da e limi ed eal-wo ld e idence on secuki- numab ea men ou comes in pa ien s wi h axSpA. 8–10 Thus, he e ec i eness o secukinumab, he impac o p e ious bDMARD o a ge ed syn he ic DMARD ( sDMARD) use on secukinumab e ec i eness in ou ine ca e, as well as he impac o ime since diagnosis ha e no been s udied in a la ge obse a ional coho o pa ien s wi h axSpA. Hence, he p ima y aim o his s udy was o de e mine he o e all secukinumab e en ion a e in Eu ope a e 12 mon hs o ea men . Seconda y aims we e o de e - mine 6-mon h e en ion a es and 6-mon h and 12-mon h inac i e disease, low-disease-ac i i y (LDA) and esponse a es. P ima y and seconda y aims we e assessed o e all as well as compa ed ac oss numbe o p io b/ sDMARDs, ac oss ime since diagnosis and ac oss Eu opean egis ies. METHODS Eu opean Spondyloa h i is Resea ch Collabo a ion Ne wo k The Eu opean Spondyloa h i is Resea ch Collabo a ion Ne wo k (Eu oSpA) 11 was ini ia ed in 2016/2017. Eu o- SpA aims o de elop and in es iga e esea ch ques ions by seconda y use o p ospec i ely collec ed eal-li e da a on pa ien s wi h SpA. 11–13 So a , he collabo a ion includes 16 Eu opean egis ies, some o which ha e been collec - ing da a om as ea ly as 1999. Resea ch ques ions ocus on ou ine ca e ea men o pa ien s wi h spondyloa - h i is (SpA) in a Eu opean con ex , h ough pooling o ele an a iables om he indi idual egis ies. All da a a e anonymised in he indi idual egis ies be o e upload h ough a secu e i ual p i a e ne wo k pipeline o he secu ed Eu oSpA se e , whe e he da a a e quali y checked and pooled be o e s a is ical analyses a e conduc ed. Pa ien s Fo his s udy, anonymised da a om pa ien s wi h axSpA ea ed wi h secukinumab in ou ine ca e om 13 coun- ies in he Eu oSpA we e uploaded and pooled: ARTIS (Sweden), RRBR (Romania), SCQM (Swi ze land), ATTRA (Czech Republic), DANBIO (Denma k), BIOBA- DASER (Spain), TURKBIO (Tu key), NOR-DMARD (No way), bio x.si (Slo enia), Reuma.p (Po ugal), GISEA (I aly), ROB-FIN (Finland) and ICEBIO (Iceland) (o de ed om highes o lowes numbe o included pa ien s). The da a we e collec ed independen ly o his s udy, ha is, by na ional quali y egis ies ha collec in o ma ion on any b/ sDMARDs. All pa ien s we e p o- spec i ely ollowed in he di e en egis ies, al hough he s udy was e ospec i ely designed wi h seconda y use o da a al eady collec ed in he egis ies, ha is, planned a e da a collec ion had aken place, bu be o e da a we e a ailable. To be included pa ien s had o be ≥18 yea s old, ha e a diagnosis o axSpA as judged by he ea ing heuma ologis , be p e iously secukinumab naï e and ha e a egis e ed s a da e o secukinumab. Assessmen s Assessmen s included demog aphics, ime since diagnosis, s a and s op da es o secukinumab ea men , p e ious b/ sDMARD ea men (including he TNFis adalimu- mab, e ane cep , in liximab, golimumab and ce olizu- mab, he cos imula o y inhibi o aba acep , he an i- B-cell agen i uximab, he in e leukin (IL)-12/IL-23 inhi- bi o us ekinumab, he IL-6 ecep o inhibi o ocilizu- mab, he IL-1 ecep o inhibi o anakin a and he sDMARDs ap emilas , ba ici inib and o aci inib), cu en smoking s a us (yes/no), body mass index (kg/m 2 ), C eac i e p o ein (CRP, mg/L), e y h ocy e sedimen a- ion a e (mm/h), isual analogue scales (0–100 mm) o pa ien ’s and e alua o ’s global assessmen s, pain and a i- gue (excep o SCQM, bio x.si and RRBR which used a0–10 nume ic a ing scale) and Heal h Assessmen Ques- ionnai e (0–3). The ollowing composi e indices we e calcula ed based on hei indi idual i ems: Ba h Ankylos- ing Spondyli is Disease Ac i i y Index (BASDAI, 0–10), 14 Ba h Ankylosing Spondyli is Func ional Index (BASFI, 0–10) 15 and Ankylosing Spondyli is Disease Ac i i y Sco e (ASDAS; including BASDAI ques ions 2, 3 and 6, pa ien ’s global assessmen and CRP). 16 17 The ollowing inac i e disease, LDA and esponse measu es we e calcula ed a 6-mon h and 12-mon h ollow-up: BASDAI emission de ined as <2, BASDAI LDA de ined as <4, 18 ASDAS inac- i e disease (<1.3), 19 ASDAS LDA (<2.1), 19 change in BAS- DAI and ASDAS, BASDAI50 esponse (a leas 50% imp o emen in BASDAI sco e o an absolu e change o 2 uni s on a 0–10 scale), 18 ASAS20/40 esponse (including RMD Open 2Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om measu es o physical unc ion, pain, in lamma ion as assessed by du a ion o mo ning s i ness and pa ien ’s global assessmen ), 20 21 ASDAS clinically impo an imp o emen (ASDAS-CII≥1.1) and ASDAS majo imp o emen (ASDAS-MI≥2.0). 22 P ima y and seconda y ou comes The p ima y ou come was he o e all 12-mon h secukinu- mab e en ion a e. Seconda y ou comes we e he o e all 6-mon h secukinumab e en ion a e, and 6-mon h and 12-mon h inac i e disease, LDA and esponse a es. P i- ma y and seconda y ou comes we e compa ed ac oss (1) numbe o p e ious b/ sDMARDs (0/1/≥2), (2) ime since diagnosis (<2/2–4/>4 yea s) and (3) he di e en Eu opean egis ies. S a is ical analyses S a is ical analyses we e pe o med acco ding o a p ede ined s a is ical analysis plan. No mally dis ibu ed da a we e p esen ed as mean (SD) and skewed da a as median (IQR). G oup compa isons o demog aphics and baseline disease ac i i y we e pe o med wi h analysis o a iance (ANOVA), K uskal-Wallis o χ² es , as app op ia e. All d ug e en ion, disease s a e and esponse analyses we e pe o med a 6-mon h and 12-mon h ollow-up. D ug e en ion was explo ed by Kaplan-Meie analyses wi h log- ank es . Cox eg ession analyses adjus ed o age, gende and ime since diagnosis we e applied o compa isons o e en ion ac oss numbe o p e ious b/ sDMARDs (0/1/≥2) and ac oss Eu opean egis ies, and adjus ed o age and gende o compa isons ac oss ime since diagnosis (<2/2–4/>4 yea s). G oup compa isons o disease s a es, changes in BAS- DAI/ASDAS and esponse a es we e pe o med wi h ANOVA, K uskal-Wallis o χ² es , as well as wi h analysis o co a iance (ANCOVA) and logis ic eg ession analyses adjus ed o age, gende and ime since diagnosis (com- pa isons ac oss numbe o p e ious b/ sDMARDs (0/1/ ≥2) and ac oss Eu opean egis ies), o age and gende (compa isons ac oss ime since diagnosis (<2/2–4/ >4 yea s)), as app op ia e. LUNDEX 23 adjus men s (c ude alue adjus ed o d ug e en ion) we e calcula ed o disease s a es. Mul i a ia e Impu a ion by Chained Equa ions (includ- ing 50 impu a ions) was pe o med o he Cox eg es- sion, ANCOVA and logis ic eg ession analyses o 300 pa ien s wi h missing da a o ime since diagnosis. The emaining analyses we e a ailable case analyses. Numbe o pa ien s wi h a ailable da a o each o he analyses a e shown in able 1 and in online supplemen al ables 1–5. Obse a ions we e censo ed by he da e o da a ex ac- ion, da e o dea h o end o egis y ollow-up, whiche e came i s . The index da e was de ined as he secukinu- mab ea men s a da e. Follow-up pe iod was de ined as he pe iod be ween index da e and he end o he 12- mon h s udy pe iod, da e o dea h o end o egis y ollow-up/cap u e, whiche e came i s . A signi icance le el o 0.05 was se . No co ec ions o mul iple compa isons we e pe o med. S a is ical analyses we e pe o med wi h R e sion 3.4.4/3.6.1 and SPSS e - sion 25. E hics The s udy was app o ed by he espec i e na ional da a p o ec ion agencies and esea ch e hical commi ees acco ding o legal egula o y equi emen s in he pa ici- pa ing coun ies. I was pe o med in acco dance wi h he Decla a ion o Helsinki and ollowed he S eng hening he Repo ing o Obse a ional S udies in Epidemiology guidelines. 24 RESULTS A o al o 1860 pa ien s wi h axSpA we e included, he eo 414 b/ sDMARD naï e pa ien s, 448 pa ien s p e iously ea ed wi h 1 b/ sDMARD and 998 pa ien s p e iously ea ed wi h 2 o mo e b/ sDMARDs. The 1 p io b/ sDMARD g oup included <10 pa ien s who had p e- iously been ea ed wi h us ekinumab and i uximab and 444 pa ien s p e iously ea ed wi h a TNFi. sDMARDs had p e iously been used by 14 pa ien s, all in he ≥2 p io b/ sDMARD g oup, including ap emilas by 10 pa ien s and o aci inib and ba ici inib by <10 pa ien s; hey had all p e iously also been ea ed wi h TNFi. The emaining 984 pa ien s had p e iously exclu- si ely been ea ed wi h di e en bDMARDs, including TNFi used by all o he pa ien s, us ekinumab by 24 pa ien s, aba acep by 27, i uximab by 12, ocilizumab by 28 and anakin a by <10 pa ien s ( able 1). In o ma ion on he modi ied New Yo k c i e ia we e a ail- able in 664 pa ien s and ul illed in 514 o hese pa ien s, and in o ma ion on he ASAS c i e ia in 963 pa ien s and ul illed in 799 o hese pa ien s. Fu he mo e, 97 pa ien s we e egis e ed as ul illing he ASAS c i e ia bu no he modi ied New Yo k c i e ia, ha is, compa ible wi h non- adiog aphicaxSpA. Pa ien s we e only included in he s udy i hey had been ollowed in he indi idual egis ies since s a o secukinumab ea men . Hence, da e o secukinumab ini ia ion had no missing cases. O he 1860 pa ien s included in he s udy, 916 pa ien s we e s ill using secuki- numab a he da e o da a ex ac ion, 659 pa ien s had a egis e ed s op da e o secukinumab, 240 pa ien s had a da e o end o ollow-up and he emaining 45 pa ien s we e assumed o ha e ended secukinumab 12 mon hs a e he las egis e ed isi , in acco dance wi h he p e- de ined s a is ical analysis plan. In o ma ion on doses was no egis e ed sys ema ically. O 828 pa ien s in whom doses we e egis e ed, 762 pa ien s ini ia ed secukinumab 150 mg/mon h and 66 pa ien s 300 mg/mon h. The pa ien s s a ed secukinumab ea men be ween Ap il 2015 and Decembe 2018. Da a cu s in he indi i- dual egis ies we e pe o med be ween Oc obe 2018 and Sep embe 2019. A o al o 1270 o he 1860 pa ien s had s a ed secukinumab ea men a leas 52 weeks Spondyloa h i is Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 3 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om Table 1 Demog aphics and baseline disease ac i i y measu es o all pa ien s, as well as compa ed ac oss numbe o p e ious b/ sDMARDs All pa ien s (n=1860) b/ sDMARD- naï e pa ien s (n=414) 1 p io b/ sDMARD (n=448) 2 o mo e p io b/ sDMARDs (n=998) P alue* Age (yea s), mean (SD), median (IQR), n a ailable 47.1 (11.9), 47 (38–56) n=1860 45.4 (11.9), 45 (36–54) n=414 46.8 (11.9), 46 (38–56) n=448 48.0 (11.8), 48 (39–57) n=998 0.001 Men, % n a ailable 55.5% n=1860 68.1% n=414 57.8% n=448 49.2% n=998 <0.001 Yea s since diagnosis, mean (SD), median (IQR) n a ailable 9.9 (9.0), 7(3–14) n=1560 8.1 (9.0), 5(1–12) n=396 10.0 (9.4), 7(3–15) n=403 10.7 (8.6), 8(4–15) n=761 <0.001 Cu en smoke s, %, n a ailable 24.6% n=1696 26.8% n=380 25.4% n=410 23.4% n=906 0.40 Pa ien ’s global assessmen (0–100), median (IQR), n a ailable 70 (50–81) n=1324 80 (60–90) n=292 64 (50–80) n=310 70 (50–82) n=722 <0.001 Physician’sglobal assessmen (0–100), median (IQR), n a ailable 45 (25–63) n=780 64 (43–78) n=175 45 (22–60) n=156 40 (20–58) n=449 <0.001 Heal h Assessmen Ques ionnai e (0–3), mean (SD), median (IQR), n a ailable 1.1 (0.6), 1.1 (0.6–1.5) n=843 1.1 (0.6), 1.1 (0.8–1.6) n=187 1.1 (0.6), 1.1 (0.6–1.5) n=162 1.1 (0.6), 1.0 (0.6–1.5) n=494 0.76 Body mass index (kg/m 2 ), median (IQR), n a ailable 27 (24–31) n=1058 27 (24–30) n=333 27 (24–31) n=274 27 (23–31) n=451 0.97 C eac i e p o ein (mg/L), median (IQR), n a ailable 8(3–25) n=1454 15 (5–31) n=337 7(3–25) n=341 6(2–22) n=776 <0.001 E y h ocy e sedimen a ion a e (mm/h), median (IQR), n a ailable 22 (9–44) n=1143 30 (14–44) n=296 24 (8–45) n=286 18 (8–42) n=561 <0.001 Pain (0–100), median (IQR), n a ailable 70 (50–81) n=1299 80 (65–90) n=288 65 (49–80) n=299 70 (50–80) n=712 <0.001 Fa igue (0–100), median (IQR), n a ailable 70 (50–82) n=1190 77 (60–90) n=266 65 (45–80) n=279 70 (50–84) n=645 <0.001 BASDAI, median (IQR), mean (SD), n a ailable 6.2 (4.6–7.6), 6.0 (2.2) n=1444 6.8 (5.2–8.0), 6.4 (2.1) n=371 5.9 (4.2–7.2), 5.6 (2.3) n=349 6.1 (4.4–7.6), 5.9 (2.2) n=724 <0.001 BASFI, median (IQR), n a ailable 5.5 (3.2–7.3) n=872 6.1 (3.2–7.6) n=191 4.8 (2.8–6.8) n=169 5.5 (3.3–7.2) n=512 0.04 ASDAS, median (IQR), n a ailable 3.6 (2.9–4.3) n=1241 4.2 (3.5–4.8) n=292 3.5 (2.7–4.2) n=297 3.5 (2.8–4.2) n=652 <0.001 Fi s b/ sDMARD ea men Adalimumab, n (%) 397 (27.5) NA 125 (27.9) 272 (27.3) 0.84 Ce olizumab, n (%) 76 (5.3) NA 27 (6.0) 49 (4.9) 0.45 E ane cep , n (%) 362 (25.0) NA 115 (25.7) 247 (24.7) 0.76 Golimumab, n (%) 170 (11.8) NA 75 (16.7) 95 (9.5) <0.001 In liximab, n (%) 357 (24.7) NA 82 (18.3) 275 (27.6) <0.001 O he , n (%) 8 (0.6) NA 4 (0.9) 4 (0.4) 0.21 Con inued RMD Open 4Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om p io o he da e o he da a cu . b/ sDMARD-naï e pa ien s we e younge , had sho e ime since diagnosis, highe baseline disease ac i i y and a highe p opo ion we e men compa ed wi h pa ien s ea ed wi h one p io , o wo o mo e p io , b/ sDMARDs. Secukinumab d ug e en ion o e all and compa ed by p e ious b/ sDMARD ea men O e all, 6-mon h and 12-mon h secukinumab e en ion a es we e 82% and 72%, espec i ely, and di e ed sig- ni ican ly (p≤0.001) ac oss numbe o p e ious b/ sDMARDs, wi h dec easing d ug e en ion a es wi h inc easing p e ious b/ sDMARD use (6-/12-mon h: b/ sDMARD naï e: 90%/84%, 1 p io b/ sDMARD: 83%/ 73%, ≥2 p io b/ sDMARDs: 78%/66%; able 2, igu e 1). When adjus ed o age, gende and ime since diagno- sis, pa ien s who had used one p e ious b/ sDMARD o wo o mo e p e ious b/ sDMARDs we e a highe isk o discon inuing secukinumab be o e 12 mon hs o ea - men compa ed wi h b/ sDMARD-naï e pa ien s (HR 1.78, 95% CI 1.29 o 2.47 and HR 2.33, 95% CI 1.74 o 3.11, espec i ely; online supplemen al igu e 1). Secukinumab e en ion acco ding o eason o wi hd awal Mo e pa ien s wi hd ew om secukinumab due o loss o e icacy (n=326) han ad e se e en s (n=110) ( igu e 2). Secukinumab e en ion a es acco ding o ime since diagnosis D ug e en ion o secukinumab was no associa ed wi h ime since diagnosis, when pa ien s we e s a i ied in o ime <2 yea s, 2–4 yea s and >4 yea s since diagnosis (online supplemen al able 3). Addi ional adjus men o age and gende ga e simila indings (6 mon hs, p=0.83; 12 mon hs, p=0.85). Secukinumab e en ion a es ac oss Eu opean coun ies Signi ican he e ogenei y in baseline demog aphics, dis- ease ac i i y measu es and p opo ions o bionaï e pa ien s ac oss di e en Eu opean coun ies we e ound (online supplemen al able 4). Secukinumab e en ion a es a e 6 and 12 mon hs o ea men a ied signi i- can ly ac oss he coun ies in Eu oSpA ( able 3, igu e 3). Adjus men o age, gende and ime since diagnosis ga e simila indings (da a no shown). Inac i e disease, LDA and esponse a es a e 6 and 12 mon hs o secukinumab ea men Median BASDAI a e 6 and 12 mon hs o secukinumab ea men we e 3.9 and 3.9, and ASDAS 2.6 and 2.5, espec i ely ( able 2). C ude/LUNDEX-adjus ed BAS- DAI<2 was achie ed by 26%/21% o he pa ien s a e 6 mon hs and 25%/16% a e 12 mon hs, and BASDAI<4 by 51%/40% o he pa ien s a e 6 mon hs and 51%/ 32% a e 12 mon hs o ea men . P opo ions o pa ien s achie ing c ude/LUNDEX-adjus ed ASDAS inac i e disease a e 6 and 12 mon hs o ea men we e 9%/7% and 11%/7%, and ASDAS low disease ac i i y 24%/19% and 27%/17%, espec i ely. A e 6 and 12 mon hs o ea men , BASDAI50 esponse was achie ed by 53% and 47%, ASAS20 esponse by 40% and 37%, ASAS40 esponse by 28% and 22%, ASDAS- CII by 49% and 46% and ASDAS-MI by 25% and 26% o he pa ien s, espec i ely ( able 2). Response a es in pa ien s ha ing ecei ed ≥3 b/ sDMARDs can be ound in online supplemen al able 5 and we e o e all compa - able o he g oup o pa ien s who had p e iously used ≥2 b/ sDMARDs. The e we e some di e ences in baseline cha ac e is ics be ween pa ien s wi h missing and non- missing da a o 6-mon h and 12-mon h esponse a es, bu hese we e no consis en ac oss he di e en esponse c i e ia (da a no shown). Disease s a es and esponse a es ac oss numbe o p e ious b/ sDMARDs C ude and LUNDEX-adjus ed inac i e disease, LDA and esponse a es a e 6 and 12 mon hs o ea men a ied s a is ically signi ican ly ac oss numbe o p e- iousb/ sDMARDs(allp≤0.002), showing dec easing e ec i eness wi h inc easing p e ious b/ sDMARD use. O e all, he nume ically highes a es we e ound in bionaï e pa ien s ( able 2, igu e 4). Adjus men o age, gende and ime since diagnosis ga e simila esul s (da a no shown). Inac i e disease, LDA and esponse a es acco ding o ime since diagnosis Disease s a es and esponse a es a 6 and 12 mon hs we e no signi ican ly di e en be ween pa ien s wi h ime since diagnosis <2 yea s, 2–4 yea s and >4 yea s, excep o achie emen o BASDAI<2 and <4 a 6 mon hs (online Table 1 Con inued All pa ien s (n=1860) b/ sDMARD- naï e pa ien s (n=414) 1 p io b/ sDMARD (n=448) 2 o mo e p io b/ sDMARDs (n=998) P alue* Missing, n (%) 76 (5.3) NA 20 (4.5) 56 (5.6) 0.40 n a ailable n=1446 NA n=448 n=998 *Compa isons be ween b/ sDMARD-naï e, 1 p io and ≥2 p io b/ sDMARD- ea ed pa ien s we e pe o med wi h χ² es , ANOVA o K uskal- Wallis, as app op ia e. ASDAS, Ankylosing Spondyli is Disease Ac i i y Sco e; BASDAI, Ba h Ankylosing Spondyli is Disease Ac i i y Index; BASFI, Ba h Ankylosing Spondyli is Func ional Index; b/ sDMARD, biologic/ a ge ed syn he ic disease-modi ying an i heuma ic d ug; csDMARD, con en ional syn he ic disease-modi ying an i heuma ic d ug. Spondyloa h i is Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 5 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om Table 2 T ea men e ec i eness a e 6 and 12 mon hs o secukinumab ea men All pa ien s (n=1860) b/ sDMARD- naï e pa ien s (n=414) 1 p io b/ sDMARD (n=448) 2 o mo e p io b/ sDMARDs (n=998) P alue* Secukinumab d ug e en ion a e, % (95% CI) 6 mon hs 82% (80–84%) 90% (87–93%) 83% (79–86%) 78% (76–81%) 0.001 12 mon hs 72% (69–74%) 84% (81–88%) 73% (69–78%) 66% (63–69%) <0.001 Median (95% CI) ime in weeks o secukinumab wi hd awal due o loss o e icacy o ad e se e en s be o e 12 mon hs† 21 (20–22) 22 (16–28) 21 (19–23) 21 (19–23) 0.21 BASDAI, median (IQR) 6 mon hs 3.9 (1.8–5.9) 2.8 (1.4–4.1) 3.0 (1.5–5.7) 4.8 (2.7–6.6) <0.001 12 mon hs 3.9 (1.9–6.3) 2.4 (1.3–3.9) 3.2 (1.7–6.0) 5.0 (2.6–6.8) <0.001 BASFI, median (IQR) 6 mon hs 3.9 (1.8–6.3) 2.4 (0.7–4.7) 4.0 (1.3–6.3) 4.4 (2.4–6.6) <0.001 12 mon hs 4.1 (1.8–6.5) 2.1 (0.5–4.3) 3.6 (1.4–6.4) 4.7 (2.7–6.7) <0.001 ASDAS, median (IQR) 6 mon hs 2.6 (1.9–3.3) 2.2 (1.7–2.7) 2.4 (1.7–3.1) 2.8 (2.1–3.6) <0.001 12 mon hs 2.5 (1.8–3.4) 1.9 (1.5–2.6) 2.3 (1.6–3.2) 2.8 (2.0–3.5) <0.001 BASDAI <2, % 6 mon hs C ude 26% 37% 35% 18% <0.001 LUNDEXadjus ed†21% 34% 28% 13% <0.001 12 mon hs C ude 25% 41% 29% 18% <0.001 LUNDEX- adjus ed† 16% 31% 18% 11% <0.001 BASDAI <4, % 6 mon hs C ude 51% 71% 60% 40% <0.001 LUNDEX- adjus ed† 40% 65% 47% 30% <0.001 12 mon hs C ude 51% 76% 56% 39% <0.001 LUNDEX- adjus ed† 32% 57% 36% 23% <0.001 ASDAS <1.3, % 6 mon hs C ude 9% 13% 13% 6% 0.001 LUNDEX- adjus ed† 7% 12% 11% 5% <0.001 12 mon hs C ude 11% 18% 15% 7% 0.002 LUNDEX- adjus ed† 7% 13% 9% 4% 0.002 ASDAS <2.1, % 6 mon hs C ude 24% 32% 26% 20% 0.002 LUNDEX- adjus ed† 19% 29% 21% 15% <0.001 12 mon hs C ude 27% 44% 27% 21% <0.001 LUNDEX- adjus ed† 17% 33% 17% 12% <0.001 Change in BASDAI om baseline o 6 mon hs Mean (SD) −2.1 (2.6) −3.7 (2.5) −2.1 (2.5) −1.4 (2.3) <0.001 Median (IQR) −1.9 (−3.9, −0.2) −3.9 (−5.4, −2.0) −1.9 (−3.8, −0.1) −1.0 (−2.8, 0.1) <0.001 Change in BASDAI om baseline o 12 mon hs Mean (SD) −2.1 (2.5) −3.3 (2.6) −2.1 (2.3) −1.4 (2.4) <0.001 Con inued RMD Open 6Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om Table 2 Con inued All pa ien s (n=1860) b/ sDMARD- naï e pa ien s (n=414) 1 p io b/ sDMARD (n=448) 2 o mo e p io b/ sDMARDs (n=998) P alue* Median (IQR) −1.6 (−3.7, −0.2) −3.4 (−5.4, −1.2) −1.9 (−3.6, −0.5) −1.1 (−2.5, 0.0) <0.001 Change in ASDAS om baseline o 6 mon hs Mean (SD) −1.1 (1.3) −2.0 (1.1) −1.1 (1.3) −0.7 (1.2) <0.001 Median (IQR) −1.1 (−2.0, −0.2) −1.9 (−2.9, −1.2) −1.1 (−2.0, −0.1) −0.6 (−1.6, 0.0) <0.001 Change in ASDAS om baseline o 12 mon hs Mean (SD) −1.1 (1.3) −2.0 (1.3) −1.2 (1.2) −0.7 (1.2) <0.001 Median (IQR) −0.9 (−2.0, −0.1) −2.0 (−3.1, −1.0) −1.2 (−2.2, −0.3) −0.5 (−1.5,-0.1) <0.001 BASDAI50 esponse, % 6 mon hs C ude 53% 79% 53% 40% <0.001 LUNDEX- adjus ed† 42% 72% 42% 30% <0.001 12 mon hs C ude 47% 67% 53% 36% <0.001 LUNDEX- adjus ed† 29% 51% 34% 21% <0.001 ASAS20 esponse, % 6 mon hs C ude 40% 66% 41% 32% <0.001 LUNDEX- adjus ed† 32% 60% 32% 24% <0.001 12 mon hs C ude 37% 69% 35% 29% <0.001 LUNDEX- adjus ed† 23% 52% 22% 17% <0.001 ASAS40 esponse, % 6 mon hs C ude 28% 57% 23% 19% <0.001 LUNDEX- adjus ed† 22% 52% 18% 14% <0.001 12 mon hs C ude 22% 55% 19% 14% <0.001 LUNDEX- adjus ed† 14% 42% 12% 8% <0.001 ASDAS-CII, % 6 mon hs C ude 49% 77% 52% 35% <0.001 LUNDEX- adjus ed† 39% 70% 41% 26% <0.001 12 mon hs C ude 46% 72% 52% 33% <0.001 LUNDEX- adjus ed† 29% 55% 33% 19% <0.001 ASDAS-MI, % 6 mon hs C ude 25% 46% 25% 15% <0.001 LUNDEX- adjus ed† 20% 42% 20% 11% <0.001 12 mon hs C ude 26% 51% 27% 17% <0.001 LUNDEX- adjus ed† 16% 39% 17% 10% <0.001 *D ug e en ion a es we e compa ed by Kaplan-Meie wi h log- ank es , con inuous measu es by ANOVA o K uskal-Wallis, as app op ia e, and p opo ions by χ² es . †Pa ien s wi h a leas 12 mon hs om secukinumab s a o da e o da a cu . ASAS20/40, Assessmen o Spondyloa h i is In e na ional Socie y 20/40 esponse; ASDAS, Ankylosing Spondyli is Disease Ac i i y Sco e; ASDAS-CII, ASDAS clinically impo an imp o emen (≥1.1); ASDAS-MI, ASDAS majo imp o emen (≥2.0); ASAS20/40, Assessmen o Spondyloa h i is In e na ional Socie y 20/40 esponse; b/ sDMARD, biologic/ a ge ed syn he ic disease-modi ying an i heuma ic d ug; BAS- DAI, Ba h Ankylosing Spondyli is Disease Ac i i y Index; BASDAI50, a leas 50% imp o emen in BASDAI sco e o an absolu e change o 2 (on a0–10 scale); BASFI, Ba h Ankylosing Spondyli is Func ional Index. Numbe o a ailable cases o each o he analyses a e shown in online supplemen al able 1. Spondyloa h i is Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 7 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om supplemen al able 3). Adjus men o age and gende ga e simila esul s. Disease s a es and esponse a es ac oss he Eu opean egis ies Disease s a es and esponse a es a e 6 and 12 mon hs o ea men a ied signi ican ly ac oss he egis ies in Eu oSpA, excep o ASDAS inac i e disease ( able 3). Adjus men o age, gende and ime since diagnosis did no change his (da a no shown). DISCUSSION In his s udy o 1860 pa ien s om 13 Eu opean coun- ies, we p esen he i s comp ehensi e eal-li e da a on e ec i eness o secukinumab in pa ien s wi h axSpA. O e all, secukinumab e en ion a es a e 6 and 12 mon hs o ea men we e high (82% and 72%, espec i ely). Impo an ly, e ec i eness di e ed signi i- can ly ac oss numbe o p e ious b/ sDMARDs, wi h bio- naï e pa ien s consis en ly ha ing nume ically be e secukinumab e en ion as well as disease s a e and esponse a es. Time since diagnosis did no impac on secukinumab d ug e en ion, inac i e disease/LDA o esponse a es, wi h ew excep ions o 6-mon h BASDAI ou comes. Signi ican di e ences be ween he Eu opean egis ies we e ound. To da e, only a ew small obse a ional s udies on secuki- numab e ec i eness in axSpA ha e been published, includ- ing a UK s udy o 76 pa ien s ha epo ed a end owa ds imp o ed 6-mon h BASDAI and BASFI esponses, 10 an I alian s udy o 39 pa ien s wi h axSpA ha epo ed good 2-yea e ec i eness o secukinumab 9 and a Ge man pilo s udy o 13 pa ien s ha epo ed 2-yea clinical imp o e- men and eg ession o spinal in lamma ion as assessed by MRI. 8 The e o e, his eal-li e, in e na ional mul icen e s udy om la ge obse a ional coho s ep esen s an impo an addi ion o he RCTs on secukinumab. In e es - ingly, da a on secukinumab e en ion om RCTs a e sca ce. In he MEASURE 1 ial, he 2-yea secukinumab e en ion was 78%, 25 and in he MEASURE 2 ial, he 3-yea e en ion a e was 86% o secukinumab 150 mg e e y 4 weeks. 6 In he MEASURE 3 ial, he 1-yea e en- ion a e was 87% in he g oup o pa ien s who we e ini ially andomised o 150 mg secukinumab, 7 which is highe han he o e all 1-yea e en ion a e o 72% in his eal-li e s udy. Compa ed o he pa ien s in he MEASURE 2 and 3 ials, he pa ien s in ou s udy we e olde (mean age 47 s 42 and 43 yea s), had lowe baseline BASDAI (mean BAS- DAI 6.0 s 6.6 and 7.0), longe ime since diagnosis (9.9 s 7.0 and 6.0 yea s), a lowe p opo ion we e TNFi-naï e (22% s 61% and 57%) and we included bo h pa ien s wi h adiog aphic axSpA and pa ien s wi h non- adiog aphic axSpA, whe eas only pa ien s wi h adio- g aphic axSpA we e included in he MEASURE 2 and 3 ials. 67 Due o hese di e ences in pa ien cha ac e is ics and, pe haps mos impo an ly in s udy design, no alid conclusion on he compa ison o secukinumab e ec i e- ness ac oss hese s udies may be d awn. The 12-mon h secukinumab e en ion a e o he b/ sDMARD-naï e pa ien s in his s udy (84%) was simila o he ecen ly epo ed 12-mon h e en ion a e o i s -line TNFi in pa ien s wi h axSpA in Eu ope (80%) 11 as well as o o he s udies on i s -line TNFi ea men . 26 Re en ion o a i s TNFi in axSpA is in gene al known o be highe han o a second o hi d TNFi. 27 O no e, we epo simila indings o secukinumab in his s udy, wi h nume i- cally highe secukinumab e en ion o b/ sDMARD-naï e pa ien s compa ed wi h pa ien s ea ed wi h one and wo o mo e p e ious b/ sDMARDs. Thus, his s udy suppo s Figu e 1 Pooled 12-mon h secukinumab e en ion a es o pa ien s wi h axial spondyloa h i is in he Eu opean Spondyloa h i is Resea ch Collabo a ion Ne wo k s a i ied by p e ious biologic/ a ge ed syn he ic disease-modi ying an i heuma ic d ug (b/ sDMARD) ea men (log- ank es ; p<0.001). Figu e 2 Secukinumab e en ion a es due o ad e se e en s (AE) and loss o e icacy (LOE, Kaplan-Meie plo ; o 29 pa ien s, i was no dis inguished by he egis ies whe he eason o wi hd awal was due o AE o LOE). RMD Open 8Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om Table 3 Re en ion, inac i e disease, LDA and esponse a es a e 6 and 12 mon hs o secukinumab ea men s a i ied ac oss Eu opean egis ies (ICEBIO (Iceland) is excluded om he able due o <10 pa ien s a secukinumab ini ia ion) Mon hs ARTIS RRBR SCQM ATTRA DANBIO BIOBADASER TURKBIO NOR- DMARD bio x.si Reuma.p GISEA ROB-FIN P alue* Re en ion a e, % (95% CI) 6 78% (74–82%) 89% (86–93%) 77% (71–83%) 88% (84–93%) 73% (67–81%) 82% (75–89%) 82% (75–91%) 76% (66–87%) 87% (80–96%) 93% (86–100%) 89% (80–99%) 70% (57–85%) <0.001 12 64% (59–69%) 85% (81–90%) 64% (58–71%) 84% (79–90%) 64% (56–73%) 75% (67–83%) <10 pa ien s 56% (43–71%) 83% (74–93%) 86% (77–96%) 86% (77–97%) 53% (40–71%) <0.001 BASDAI<2, % 6 10% 56% 17% 35% 11% 0% 42% 12% 25% 11% 9% 25% <0.001 12 9% 71% 9% 44% 15% 20% <10 pa ien s 7% 17% 21% 19% 33% <0.001 BASDAI<4, % 6 31% 89% 34% 67% 26% 38% 64% 45% 54% 36% 46% 43% <0.001 12 31% 96% 35% 73% 36% 47% <10 pa ien s 33% 46% 59% 63% 62% <0.001 ASDAS<1.3, % 6 7% 13% 8% 9% 4% <10 pa ien s 18% 7% 0% 5% 13% 8% 0.09 12 5% 15% 8% 20% 12% 14% <10 pa ien s 0% 0% 8% 23% 10% 0.11 ASDAS<2.1, % 6 15% 35% 18% 32% 16% <10 pa ien s 25% 27% 27% 11% 35% 25% <0.001 12 18% 52% 19% 31% 19% 57% <10 pa ien s 7% 10% 27% 23% 20% <0.001 BASDAI50 esponse, % 6 34% 86% 29% 68% 28% 33% 52% 36% 57% 53% 28% 32% <0.001 12 21% 92% 24% 68% 29% 50% <10 pa ien s 13% 72% 53% 31% 37% <0.001 ASAS20 esponse, % 6 31% –30% 63% 27% –46% –<10 pa ien s ––<10 pa ien s <0.001 12 18% –31% 74% 36% –<10 pa ien s –<10 pa ien s ––<10 pa ien s <0.001 ASAS40 esponse, % 6 18% –24% 52% 12% –29% –<10 pa ien s ––<10 pa ien s <0.001 12 7% –15% 55% 21% –<10 pa ien s –<10 pa ien s ––<10 pa ien s <0.001 *Compa isons ac oss he egis ies we e pe o med wi h Kaplan-Meie wi h log- ank es o e en ion a es and χ² es o disease s a es and esponse a es. –, no collec ed; ASAS20/40, Assessmen o Spondyloa h i is In e na ional Socie y 20/40 esponse; ASDAS, Ankylosing Spondyli is Disease Ac i i y Sco e; ASDAS-CII, ASDAS clinically impo an imp o emen (≥1.1); ASDAS-MI, ASDAS majo imp o emen (≥2.0); ASAS20/40, Assessmen o Spondyloa h i is In e na ional Socie y 20/40 esponse; BASDAI, Ba h Ankylosing Spondyli is Disease Ac i i y Index; BASDAI50, 50% imp o emen in BASDAI; BASFI, Ba h Ankylosing Spondyli is Func ional Index. Numbe o a ailable cases o each o he analyses a e shown in online supplemen al able 2. Spondyloa h i is Michelsen B, e al.RMD Open 2020;6:e001280. doi:10.1136/ mdopen-2020-001280 9 by copy igh . on Feb ua y 11, 2021 a Uni e sidade de Lisboa. P o ec edh p:// mdopen.bmj.com/RMD Open: i s published as 10.1136/ mdopen-2020-001280 on 19 Sep embe 2020. Downloaded om