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