Risk ac o s o eac i a ion o clinical disease ac i i y in mul iple scle osis a e na alizumab
cessa ion
Mus onen, Tiina, BMa,#; Rauma, Ilkka, MDb,#,*; Ha ikainen, Päi i, MD, PhDa,c; K üge ,
Johanna, MD, PhDd,e; Nii anen, Ma ja, MDa; Selande , Tuomas, M.Sc. ; Simula, Saka i, MD,
PhDg; Remes, Anne M, MD, PhDd,e; Kuusis o, Hanna, MD, PhDb,h
aKuopio Uni e si y Hospi al, Depa men o Neu ology, Puijonlaakson ie 2, P.O. Box 100,
70029 KYS, Finland
bTampe e Uni e si y Hospi al, Depa men o Neu ology, Teiskon ie 35, 33520 Tampe e,
Finland
cUni e si y o Eas e n Finland, Depa men o Neu ology, Yliopis on an a 1, 70210 Kuopio,
Finland
dUni e si y o Oulu, Resea ch Uni o Clinical Neu oscience, P.O. Box 8000, 90014
Uni e si y o Oulu, Finland
eNo he n Os obo hnia Hospi al Dis ic , MRC Oulu, P.O. Box 8000, 90014 Uni e si y o
Oulu, Finland
Kuopio Uni e si y Hospi al, Science Se ice Cen e , Puijonlaakson ie 2, P.O. Box 100,
70029 KYS, Finland
gMikkeli Cen al Hospi al, Depa men o Neu ology, Po assalmenka u 35-37, 50100
Mikkeli, Finland
hUni e si y o Eas e n Finland, Depa men o Heal h and Social Managemen ,
Yliopis on an a 1, 70210 Kuopio, Finland
#Equal con ibu ion / sha ed i s au ho ship
*Co esponding au ho (E-mail add ess: [email p o ec ed])
This is he accep ed manusc ip o he a icle, which has been published in
Mul iple Scle osis and Rela ed Diso de s. 2020, 38,101498.
h ps://doi.o g/10.1016/j.msa d.2019.101498
Highligh s o he s udy
- Clinical elapses we e documen ed in 36 % o pa ien s be ween 0-12 mon hs
- Co icos e oid- ea ed elapses occu ed in 30 % o pa ien s be ween 0-12 mon hs
- High disease ac i i y and EDSS ≥ 5.5 be o e na alizumab p edic ed eac i a ion
- Subsequen ea men s ailed o p e en eac i a ion
- Washou ime > 3 mon hs was associa ed wi h an inc eased eac i a ion isk
Abs ac
Backg ound
Na alizumab (NTZ) is widely used o highly ac i e elapsing- emi ing mul iple scle osis
(MS). In lamma o y disease ac i i y o en e u ns a e NTZ ea men discon inua ion. We
aimed o iden i y p edic i e ac o s o such eac i a ion in a eal-li e se ing.
Me hods
We conduc ed a e ospec i e su ey in ou Finnish hospi als. A compu e -based sea ch was
used o iden i y all pa ien s who had ecei ed NTZ o mul iple scle osis. Pa ien s we e
included i hey had ecei ed a leas six NTZ in usions, had discon inued ea men o a
leas h ee mon hs, and ollow-up da a was a ailable o a leas 12 mon hs a e
discon inua ion. Al oge he 89 pa ien s we e analyzed wi h Cox eg ession model o iden i y
isk ac o s o eac i a ion, de ined as ha ing a co icos e oid- ea ed elapse.
Resul s
A 6 and 12 mon hs a e discon inua ion o NTZ, a elapse was documen ed in 27.0 % and
35.6 % o pa ien s, whe eas co icos e oid- ea ed elapses we e documen ed in 20.2 % and
30.3 % o pa ien s, espec i ely. A highe numbe o elapses du ing he yea p io o he
in oduc ion o NTZ was associa ed wi h a signi ican ly highe isk o eac i a ion a 6
mon hs (Haza d Ra io [HR] 1.65, p<0.001) and a 12 mon hs (HR 1.53, p<0.001). Expanded
NTZ = na alizumab, MS = mul iple scle osis, HR = haza d a io, EDSS = Expanded Disabili y S a us
Scale, DMD = disease-modi ying d ug, RRMS = elapsing- emi ing mul iple scle osis, VCAM-1 =
ascula -cell adhesion molecule 1, CNS = cen al ne ous sys em, PML = p og essi e mul i ocal
leukoencephalopa hy, SPMS = seconda y-p og essi e mul iple scle osis, MRI = magne ic esonance
imaging, CI = con idence in e al, SD = s anda d de ia ion
Disabili y S a us Scale (EDSS) o 5.5 o highe be o e NTZ ini ia ion was associa ed wi h a
highe eac i a ion isk a 6 mon hs (HR 3.70, p=0.020). Subsequen disease-modi ying d ugs
(DMDs) ailed o p e en eac i a ion o MS in his coho . Howe e , when subsequen
DMDs we e used, a washou ime longe han 3 mon hs was associa ed wi h a highe
eac i a ion isk a 6 mon hs ega dless o whe he pa ien s we e swi ched o i s -line (HR
7.69, p=0.019) o second-line he apies (HR 3.94, p=0.035). Gende , age, ime since
diagnosis, and he numbe o NTZ in usions we e no associa ed wi h an inc eased isk o
eac i a ion.
Conclusion
High disease ac i i y and a high le el o disabili y p io o NTZ ea men seem o p edic
disease eac i a ion a e ea men cessa ion. When swi ching o subsequen DMDs, he
washou ime should no exceed 3 mon hs. Howe e , subsequen DMDs ailed o p e en he
eac i a ion o MS in his coho .
Keywo ds
Mul iple scle osis; na alizumab; discon inua ion; eac i a ion; ebound
1. In oduc ion
Na alizumab (NTZ) is a humanized monoclonal an ibody used in he ea men o elapsing-
emi ing mul iple scle osis (RRMS)(Cle ico e al., 2017). I is adminis e ed in a enously in
e e y ou weeks. NTZ has been p o en e ec i e in educing he ecu ence o elapses in
mul iple scle osis (MS), and i is gene ally used in pa ien s wi h a highly ac i e cou se o
disease o a poo esponse o he i s -line he apies o MS(Kappos e al., 2011; T amace e e
al., 2015). By binding o he 4 subuni on 41 in eg in, NTZ blocks he binding o hese
in eg ins o he ascula -cell adhesion molecule 1 (VCAM-1), which is exp essed on he
endo helial cells o blood essels in he cen al ne ous sys em (CNS)(Lége e al., 1997;
Yednock e al., 1992). As a esul , he mig a ion o T-lymphocy es om he ci cula ion o he
CNS is p e en ed. The he apeu ic e ec o NTZ is mos ly explained by his egula ion o T-
lymphocy e adhesion and mig a ion ac oss he blood-b ain ba ie , bu o he α4-media ed
e ec s o NTZ ha e also been sugges ed(Rice e al., 2005).
The use o NTZ is limi ed due o he isk o p og essi e mul i ocal leukoencephalopa hy
(PML)(Tan and Ko alnik, 2010). The isk o PML is inc eased in pa ien s wi h long ea men
pe iods, p io immunosupp essi e ea men , and posi i e s a us wi h espec o an i-JC i us
an ibodies(Bloomg en e al., 2012). I he isk is conside ed oo high, swi ching o an
al e na i e disease-modi ying d ug (DMD) should be conside ed.
In Finland, na ional ea men guidelines a e ollowed when selec ing DMDs o MS(Mul iple
Scle osis: Cu en Ca e Guidelines, 2019). In he Finnish na ional guidelines, NTZ is
posi ioned ei he as a i s -line o second-line he apy o highly ac i e RRMS wi h no an i-
JC i us an ibodies. Cessa ion o ea men is ad ised i se ocon e sion occu s. NTZ is
o icially licensed only o RRMS in Finland, bu i is some imes used in seconda y-

p og essi e mul iple scle osis (SPMS) pa ien s who expe ience clinical elapses(Mul iple
Scle osis: Cu en Ca e Guidelines, 2019).
NTZ is clea ed om ci cula ion in app oxima ely wo mon hs a e discon inua ion o
ea men , bu some esidual e ec s may pe sis o up o 6 mon hs(O’Conno e al., 2011;
S ü e e al., 2006). As expec ed, eac i a ion o MS has been shown o occu du ing he i s
yea a e discon inua ion o NTZ in some pa ien s(Fox e al., 2014; Gueguen e al., 2014;
Ha la e al., 2011; Ia aldano e al., 2015; Ke b a e al., 2011; Lo Re e al., 2015; O’Conno
e al., 2011; Salho e -Polanyi e al., 2014; Wes and C ee, 2010). A ecen sys ema ic e iew
and me a-analysis o six s udies demons a ed ha younge age, highe numbe o elapses
and gadolinium-enhancing lesions be o e ini ia ion o ea men as well as ewe NTZ
in usions we e associa ed wi h an inc eased isk o disease eac i a ion a e cessa ion o
ea men (P ospe ini e al., 2019).
The e a e no es ablished guidelines on how o ea MS pa ien s discon inuing NTZ he apy,
bu ecen epo s ha e sugges ed ha subsequen ea men wi h o he DMDs should be
ini ia ed wi hin 3 mon hs a e discon inua ion in o de o p e en disease
eac i a ion(Ia aldano e al., 2015; Jokubai is e al., 2014; Kappos e al., 2015; Lo Re e al.,
2015; Salho e -Polanyi e al., 2014). Howe e , mos o he cu en e idence comes om
obse a o y s udies wi h he e ogeneous s udy se ings, and only ew andomized ials ha e
been published(Fox e al., 2014; Kappos e al., 2015; O’Conno e al., 2011). Ou pu pose
was o e alua e he p edic i e ac o s o pos -NTZ disease eac i a ion in an unselec ed
clinical coho o MS pa ien s in a eal-li e se ing.
2. Ma e ial and me hods
2.1 S udy popula ion
This e ospec i e s udy was ca ied ou using da a om ou Finnish hospi als co e ing a
ca chmen a ea o 1.3 million esiden s. Th ee uni e si y hospi als (Kuopio Uni e si y
Hospi al, Tampe e Uni e si y Hospi al and Oulu Uni e si y Hospi al) om di e en pa s o
Finland and one medium-sized cen al hospi al (Cen al Hospi al o Mikkeli) we e chosen o
ep esen MS ea men in Finland. The s udy was app o ed by he Resea ch E hics
Commi ee o he No he n Sa o Hospi al Dis ic , Kuopio, Finland, and had an ins i u ional
app o al om each pa icipa ing hospi al.
MS pa ien s we e iden i ied by a compu e -based sea ch using he ICD-8, -9 o -10 diagnosis
o MS and ea men wi h NTZ as sea ch c i e ia. Pa ien s we e included in he s udy i hey
had ecei ed a leas six consecu i e in usions o NTZ be o e he ea men was discon inued
and ollow-up da a was a ailable o a leas 12 mon hs a e he las in usion. A
discon inua ion was de ined as a h ee-mon h pe iod wi hou any NTZ in usions. Sho e gaps
be ween in usions we e no conside ed ele an . We iden i ied a o al o 101 MS pa ien s who
had discon inued NTZ ea men in yea s 2009-2016, and 89 o hem me he inclusion
c i e ia. A lowcha displaying he selec ion o he s udy coho is shown in Figu e 1.
2.2 Me hods
The pa ien eco ds we e sys ema ically e iewed om he ime o he i s symp om o he
la es a ailable con ac wi h he hospi al. Da a was collec ed om bo h pape a chi es and he
hospi al dis ic s’ elec onic pa ien in o ma ion sys ems. The ollowing a iables we e
collec ed: gende ; onse symp om o MS; ime om diagnosis o he ini ia ion o NTZ
ea men ; exis ence o gadolinium-enhancing lesions in he p e-NTZ magne ic esonance
imaging (MRI) scan; numbe o NTZ in usions; ad e se e en s du ing NTZ ea men ;
p ima y eason o he discon inua ion o NTZ; p io and subsequen DMDs; washou ime
be ween DMDs; and all cou ses o co icos e oid ea men . Age was collec ed bo h a he
ime o diagnosis and a NTZ ini ia ion. Expanded Disabili y S a us Scale (EDSS) was
collec ed a diagnosis, a NTZ ini ia ion, and a NTZ discon inua ion. The numbe o elapses
du ing he yea be o e NTZ ini ia ion and he yea a e NTZ discon inua ion we e collec ed.
In ou analysis, he onse symp om o MS was also ega ded as a elapse. Relapses we e
collec ed in wo ca ego ies. Fi s , all epo ed elapses we e collec ed ega dless o whe he
hey equi ed co icos e oid ea men o no . Second, only elapses which equi ed
co icos e oid ea men we e collec ed. The la e we e used o de ine eac i a ion in he
s a is ical analysis.
Reac i a ion was de ined as ha ing expe ienced a leas one co icos e oid- ea ed elapse
a e NTZ discon inua ion. Rebound was de ined as an inc ease in he yea ly numbe o all
elapses a e he discon inua ion o NTZ ea men when compa ed o he yea be o e he
ini ia ion o NTZ. Washou ime was de ined as he ime be ween he las in usion o NTZ
and he ini ia ion o he ollowing ea men . In he analysis, EDSS was ca ego ized in o wo
g oups wi h a cu poin o 5.5.
2.3 S a is ical analysis
Uni a ia e Cox eg ession model was i s used o iden i y indi idual a iables associa ed
wi h he isk o eac i a ion a 6 and 12 mon hs o ollow-up. Va iables wi h s a is ically
signi ican associa ions in he uni a ia e model we e hen e-analyzed wi h mul i a ia e Cox
eg ession. The e ec o subsequen DMDs adminis e ed a e he cessa ion o NTZ
ea men was analyzed using uni a ia e Cox eg ession wi h pa ien as a andom e ec , and
subg oup analysis was pe o med o de e mine whe he a washou o 0-3 mon hs o longe
han 3 mon hs was associa ed wi h he isk o eac i a ion. Resul s o he Cox eg ession
analyses a e shown as haza d a ios (HR) wi h 95 % con idence in e als (CI). S a is ical
analysis o he isk o ebound was no pe o med, as he e we e only ew cases ep esen ing
possible ebound in he coho . Da a was exp essed as means wi h s anda d de ia ions (SD)
o equencies wi h pe cen ages. S a is ical analysis was pe o med using SPSS S a is ics 24.0
and R e sion 3.5.1. S a is ical signi icance was de ined as wo- ailed p < 0.05.
con i med i s exis ence(O’Conno e al., 2011). We de ined ebound as an inc ease in he
numbe o yea ly elapses a e discon inua ion o NTZ when compa ed o he yea be o e
NTZ ini ia ion and disco e ed ha 9 % o ou pa ien s had expe ienced ebound ac i i y. This
is somewha lowe han wha has been epo ed in he majo i y o ea lie epo s(Gueguen e
al., 2014; Ke b a e al., 2011; Lo Re e al., 2015), bu almos simila o wha was epo ed in
wo ea lie s udies(Salho e -Polanyi e al., 2014; Sangalli e al., 2014).
The s udy has limi a ions ha should be no ed. Due o he e ospec i e se ing, some da a
we e missing. Al hough i is a common cus om in Finland o pa ien s using DMDs o a end
egula ollow-up isi s wi h neu ological examina ions, EDSS was no always documen ed.
Fu he mo e, a subs an ial pa o MRI da a was missing. The e o e, we could no use i in he
eg ession analysis. When desc ibing p e-NTZ MRI, we only epo ed whe he gadolinium-
enhancing lesions we e p esen , as he exac numbe o lesions was no epo ed o e e y
pa ien .
We ind he s eng h o his s udy o be i s co e age o a la ge ca chmen a ea, he inclusion
o ou hospi als om di e en pa s o Finland, and he use o an unselec ed eal-li e case
se ies. The exis ence o ou na ional ea men guidelines makes ou da a uni o m and well
ep esen a i e o he ac ual ea men ha Finnish MS pa ien s ecei ed in yea s 2009-2016.
Due o ou na ional ea men guidelines, he indica ions o using di e en DMDs o
educing disease ac i i y and p esc ibing co icos e oids o elapses in MS a e conco dan
be ween di e en s udy cen e s.
Since app oxima ely a i h o MS pa ien s discon inuing NTZ seem o su e om
eac i a ion ega dless o he du a ion o hei ea men , we sugges ha NTZ should only be
ini ia ed wi h he pu pose o using he ea men o long pe iods. None o he he apeu ic
s a egies used in his coho we e able o con ol he e u n o disease ac i i y. In he u u e,

he e icacy o he mo e ecen ly app o ed DMDs in p e en ing pos -NTZ disease
eac i a ion should be e alua ed. Un il hen, close a en ion should be paid on pa ien
selec ion, ega ding e ile women wi h amily plans in pa icula . Washou imes should be
kep as sho as possible a e NTZ cessa ion.
5. Conclusions
Discon inua ion o NTZ ea men may lead o a ma ked eac i a ion o MS. High disease
ac i i y and a high le el o disabili y p io o NTZ ini ia ion seem o p edic such eac i a ion,
which could no be p e en ed wi h subsequen DMDs. A washou ime longe han 3 mon hs
was a isk ac o o pos -NTZ disease eac i a ion.
6. Re e ences
Bloomg en, G., Richman, S., Ho e mans, C., Sub amanyam, M., Goelz, S., Na a ajan, A.,
Lee, S., Pla ina, T., Scanlon, J. V., Sand ock, A., Bozic, C., 2012. Risk o Na alizumab-
Associa ed P og essi e Mul i ocal Leukoencephalopa hy. N. Engl. J. Med. 366, 1870–
1880. h ps://doi.o g/10.1056/NEJMoa1107829
Cle ico, M., A usi, C., Libe o, A., Rolla, S., Ba dina, V., Ba be o, P., Me can i, S., Du elli,
L., 2017. Na alizumab in Mul iple Scle osis: Long-Te m Managemen . In . J. Mol. Sci.
18, 940. h ps://doi.o g/10.3390/ijms18050940
Co eale, J., Gai án, M.I., Ys aeli , M.C., Fiol, M.P., 2017. P og essi e mul iple scle osis:
om pa hogenic mechanisms o ea men . B ain 140, 527–546.
h ps://doi.o g/10.1093/b ain/aww258
Fox, R.J., C ee, B.A.C., De Sèze, J., Gold, R., Ha ung, H.-P., Je e y, D., Kappos, L.,
Kau man, M., Mon albán, X., Weins ock-Gu man, B., Ande son, B., Na a ajan, A.,
Ticho, B., Duda, P., RESTORE, 2014. MS disease ac i i y in RESTORE: a andomized
24-week na alizumab ea men in e up ion s udy. Neu ology 82, 1491–8.
h ps://doi.o g/10.1212/WNL.0000000000000355
Gueguen, A., Roux, P., Deschamps, R., Moulignie , A., Bensa, C., Sa a o sky, J., He an, F.,
Gou , O., 2014. Abno mal in lamma o y ac i i y e u ns a e na alizumab cessa ion in
mul iple scle osis. J. Neu ol. Neu osu g. Psychia y 85, 1038–1040.
h ps://doi.o g/10.1136/jnnp-2014-307591
Ha la, J., Ge des, L.A., Meinl, I., K umbholz, M., Fabe , H., Webe , F., Pellko e , H.L.,
Hohl eld, R., Kümp el, T., 2011. De-escala ion om na alizumab in mul iple scle osis:
Recu ence o disease ac i i y despi e swi ching o gla i ame ace a e. J. Neu ol. 258,
1665–1669. h ps://doi.o g/10.1007/s00415-011-5996-y
Ia aldano, P., Lucisano, G., Pozzilli, C., B escia Mo a, V., Ghezzi, A., Mille io ini, E.,
Pa i, F., Luga esi, A., Zima o e, G.B., Ma osu, M.G., Ama o, M.P., Be olo o, A.,
Be gamaschi, R., G anella, F., Coniglio, G., Tedeschi, G., Sola, P., Lus, G., Fe ò, M.T.,
Iuliano, G., Co ea, F., P o i, A., Ca alla, P., Gua eschi, A., Rodeghe , M., Paolicelli, D.,
To o ella, C., Lepo e, V., P ospe ini, L., Saccà, F., Ba oncini, D., Comi, G., 2015.
Fingolimod e sus in e e on be a/gla i ame ace a e a e na alizumab suspension in
mul iple scle osis. B ain 138, 3275–3286. h ps://doi.o g/10.1093/b ain/aw 260
Jokubai is, V.G., Li, V., Kalincik, T., Izquie do, G., Hodgkinson, S., Al oughani, R.,
Lechne -Sco , J., Luga esi, A., Duque e, P., Gi a d, M., Ba ne , M., G and’Maison, F.,
T ojano, M., Slee, M., Giuliani, G., Shaw, C., Boz, C., Spi ale i, D.L.A., Ve heul, F.,
Haa sen, J., Liew, D., Bu zkue en, H., MSBase S udy G oup, 2014. Fingolimod a e
na alizumab and he isk o sho - e m elapse. Neu ology 82, 1204–11.
h ps://doi.o g/10.1212/WNL.0000000000000283
Kappos, L., Radue, E.-W., Comi, G., Mon alban, X., Bu zkue en, H., Wiendl, H.,
Gio annoni, G., Ha ung, H.-P., De uss, T., Naegelin, Y., Sp enge , T., Muelle -Lenke,
N., G i i hs, S., on Rosens iel, P., Go schalk, R., Zhang, Y., Dahlke, F., Tomic, D.,
TOFINGO s udy g oup, 2015. Swi ching om na alizumab o ingolimod: A
andomized, placebo-con olled s udy in RRMS. Neu ology 85, 29–39.
h ps://doi.o g/10.1212/WNL.0000000000001706
Kappos, L, Hi sch, H H, Radü, E., Kappos, Ludwig, Ba es, D., Edan, G., û e E aksoy, M.,
Ga cia-Me ino, A., G igo iadis, N., Ha ung, H.-P., Ha do á, E., Hille , J., Hohl eld,
R., K emenchu zky, M., Lyon-Caen, O., Mille , A., Pozzilli, C., Ra nbo g, M., Saida,
T., Sindic, C., Vass, K., Cli o d, D.B., Hause , S., Majo , E.O., O, P.W., Weine , H.L.,
Clane , M., Gold, R., Hi sch, Hans H, Radü, E.-W., Soelbe g Sø ensen, P., King, J.,
2011. Na alizumab ea men o mul iple scle osis: upda ed ecommenda ions o
pa ien selec ion and moni o ing. Lance Neu ol. 10, 745–758.
h ps://doi.o g/10.1016/S1474-4422(11)70149-1
Ke b a , A., Le Page, E., Le ay, E., Anani, T., Cous ans, M., Deso meaux, C., Guiziou, C.,
Kassio is, P., Lallemen , F., Laplaud, D., Di aison, P., Rouha , F., Sa o i, E., Wa di, R.,
Wie lewski, S., Edan, G., 2011. Na alizumab and d ug holiday in clinical p ac ice: An
obse a ional s udy in e y ac i e elapsing emi ing Mul iple Scle osis pa ien s. J.
Neu ol. Sci. 308, 98–102. h ps://doi.o g/10.1016/j.jns.2011.05.043
Lége , O.J., Yednock, T.A., Tanne , L., Ho ne , H.C., Hines, D.K., Keen, S., Saldanha, J.,
Jones, S.T., F i z, L.C., Bendig, M.M., 1997. Humaniza ion o a mouse an ibody agains
human alpha-4 in eg in: a po en ial he apeu ic o he ea men o mul iple scle osis.
Hum. An ibodies 8, 3–16.
Lo Re, M., Capobianco, M., Ragonese, P., Realmu o, S., Malucchi, S., Be chialla, P., Salemi,
G., Be olo o, A., 2015. Na alizumab Discon inua ion and T ea men S a egies in
Pa ien s wi h Mul iple Scle osis (MS): A Re ospec i e S udy om Two I alian MS
Cen e s. Neu ol. The . 4, 147–57. h ps://doi.o g/10.1007/s40120-015-0038-9
Lublin, F.D., 2014. New mul iple scle osis pheno ypic classi ica ion. Eu . Neu ol. 72, 1–5.
h ps://doi.o g/10.1159/000367614
Mi a alle, A., Jensen, R., Kinkel, R.P., 2011. Immune econs i u ion in lamma o y synd ome
in pa ien s wi h mul iple scle osis ollowing cessa ion o na alizumab he apy. A ch.
Neu ol. 68, 186–91. h ps://doi.o g/10.1001/a chneu ol.2010.257
Mul iple Scle osis: Cu en Ca e Guidelines, 2019. Wo king g oup appoin ed by he Finnish
Medical Socie y Duodecim and he Finnish Neu ological Socie y [WWW Documen ].
URL h ps://www.kaypahoi o. i/en/ccs00067 (accessed 2.26.19).

O’Conno , P.W., Goodman, A., Kappos, L., Lublin, F.D., Mille , D.H., Polman, C., Rudick,
R.A., Aschenbach, W., Lucas, N., 2011. Disease ac i i y e u n du ing na alizumab
ea men in e up ion in pa ien s wi h mul iple scle osis. Neu ology 76, 1858–1865.
h ps://doi.o g/10.1212/WNL.0b013e31821e7c8a
Papeix, C., Vukusic, S., Casey, R., Deba d, N., S anko , B., M ejen, S., Uh y, Z., Van
Ganse, E., Cas o , A., Clane , M., Lube zki, C., Con a eux, C., 2016. Risk o elapse
a e na alizumab wi hd awal. Neu ol. - Neu oimmunol. Neu oin lamma ion 3, e297.
h ps://doi.o g/10.1212/NXI.0000000000000297
P ospe ini, L., Kinkel, R.P., Mi a alle, A.A., Ia aldano, P., Fan accini, S., 2019. Pos -
na alizumab disease eac i a ion in mul iple scle osis: sys ema ic e iew and me a-
analysis. The . Ad . Neu ol. Diso d. 12, 175628641983780.
h ps://doi.o g/10.1177/1756286419837809
Rice, G.P.A., Ha ung, H.-P., Calab esi, P.A., 2005. An i- 4 in eg in he apy o mul iple
scle osis: Mechanisms and a ionale. Neu ology 64, 1336–1342.
h ps://doi.o g/10.1212/01.WNL.0000158329.30470.D0
Salho e -Polanyi, S., Baumga ne , A., K aus, J., Maida, E., Schmied, M., Leu meze , F.,
2014. Wha o expec a e na alizumab cessa ion in a eal-li e se ing. Ac a Neu ol.
Scand. 130, 97–102. h ps://doi.o g/10.1111/ane.12250
Sangalli, F., Moiola, L., Fe è, L., Radaelli, M., Ba cella, V., Rodeghe , M., Colombo, B.,
Ma inelli Boneschi, F., Ma inelli, V., Comi, G., 2014. Long- e m managemen o
na alizumab discon inua ion in a la ge monocen ic coho o mul iple scle osis pa ien s.
Mul . Scle . Rela . Diso d. 3, 520–526. h ps://doi.o g/10.1016/j.msa d.2014.04.003
S ü e, O., Ma a, C.M., Je ome, K.R., Cook, L., C a ens, P.D., Cepok, S., F ohman, E.M.,
Phillips, T., A end , G., Hemme , B., Monson, N.L., Racke, M.K., 2006. Immune
su eillance in mul iple scle osis pa ien s ea ed wi h na alizumab. Ann. Neu ol. 59,
743–747. h ps://doi.o g/10.1002/ana.20858
Tan, C.S., Ko alnik, I.J., 2010. P og essi e mul i ocal leukoencephalopa hy and o he
diso de s caused by JC i us: clinical ea u es and pa hogenesis. Lance Neu ol.
h ps://doi.o g/10.1016/S1474-4422(10)70040-5
T amace e, I., Del Gio ane, C., Salan i, G., D’Amico, R., Filippini, G., 2015.
Immunomodula o s and immunosupp essan s o elapsing- emi ing mul iple scle osis:
a ne wo k me a-analysis. Coch ane Da abase Sys . Re .
h ps://doi.o g/10.1002/14651858.CD011381.pub2
Vellinga, M.M., Cas elijns, J.A., Ba kho , F., Ui dehaag, B.M.J., Polman, C.H., 2008.
Pos wi hd awal ebound inc ease in T2 lesional ac i i y in na alizumab- ea ed MS
pa ien s. Neu ology 70, 1150–1. h ps://doi.o g/10.1212/01.wnl.0000265393.03231.e5
Wes , T.W., C ee, B.A.C., 2010. Na alizumab dosage suspension: A e we helping o hu ing?
Ann. Neu ol. 68, 395–399. h ps://doi.o g/10.1002/ana.22163
Yednock, T.A., Cannon, C., F i z, L.C., Sanchez-Mad id, F., S einman, L., Ka in, N., 1992.
P e en ion o expe imen al au oimmune encephalomyeli is by an ibodies agains α4βl
in eg in. Na u e 356, 63–66. h ps://doi.o g/10.1038/356063a0
Figu e 1. The selec ion o he s udy coho . NTZ = na alizumab.
101 pa ien s who had discon inued NTZ
ea men be ween yea s 2009-2016
89 pa ien s included in he analysis
13 ea men -nai e pa ien s
76 pa ien s swi ched om o he
ea men s
9 pa ien s excluded o ecei ing < 6
in usions o NTZ
3 pa ien s excluded o ha ing < 12
mon hs o ollow-up
Table 1. Clinical cha ac e is ics o he s udy coho (n=89). SD = s anda d de ia ion, NTZ =
na alizumab, EDSS = Expanded Disabili y S a us Scale, PML = p og essi e mul i ocal
leukoencephalopa hy. *Posi i e an i-JC i us an ibodies, long ea men pe iod and/o p io
immunosupp essi e ea men
Pa ien s wi h a leas
one elapse a 6
mon hs a e cessa ion
(n=24)
Pa ien s wi h no
elapses a 6 mon hs
a e cessa ion
(n=65)
All pa ien s
(n=89)
Female gende , n (%)
17 (70.8 %)
46 (70.8 %)
63 (70.8 %)
Age a he ime o diagnosis, yea s, ange (mean ±SD)
17-50 (27.9 9.2)
15-55 (31.48.9)
15-55 (30.4 ±9.0)
Age a NTZ ini ia ion, yea s, ange (mean ±SD)
21-63 (34.511.2)
20-56 (36.69.6)
20-63 (36.0 ±10.1)
Time om diagnosis a NTZ ini ia ion, yea s, ange (mean ±SD)
0-21 (6.25.8)
0-25 (5.35.6)
0-25 (5.5 ±5.6)
EDSS a he ime o diagnosis, ange (mean ±SD)
1.0-6.0 (2.61.6)
0-5.0 (2.01.3)
0-6.0 (2.2 ±1.4)
EDSS a NTZ ini ia ion, ange (mean ±SD)
1.0-7.5 (4.01.8)
0-7.0 (3.41.8)
0-7.5 (3.6 ±1.8)
Du a ion o NTZ ea men
< 12 mon hs, n (%)
12-36 mon hs, n (%)
> 36 mon hs, n (%)
4 (16.7 %)
15 (62.5 %)
5 (20.8 %)
9 (13.8 %)
38 (58.5%)
18 (27.7 %)
13 (14.6 %)
53 (59.6 %)
23 (25.8 %)
P ima y eason o he cessa ion o NTZ ea men ,
Risk o PML conside ed oo high*, n (%)
Ine icacy o ea men , n (%)
P egnancy plans o p egnancy, n (%)
Ad e se e en s, n (%)
Di icul ies wi h pe iphe al enous cannula ion, n (%)
Pa ien ’s own wish o discon inue ea men , n (%)
11 (45.8 %)
7 (29.2%)
4 (16.7%)
1 (4.2 %)
1 (4.2%)
0 (0 %)
50 (76.9 %)
9 (13.8%)
3 (4.6%)
2 (3.1 %)
0 (0 %)
1 (1.5 %)
61 (68.5 %)
16 (18.0 %)
7 (7.9 %)
3 (3.4 %)
1 (1.1 %)
1 (1.1 %)