BioMed Cen al
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BMC Musculoskele al Diso de s
Open Access
Resea ch a icle
DAS-28-based EULAR esponse and HAQ imp o emen in
heuma oid a h i is pa ien s swi ching be ween TNF an agonis s
Fede ico Na a o-Sa abia1, Dolo es Ruiz-Mon esinos1, Blanca He nandez1,
Vic o ia Na a o-Compán1, Sa a Ma sal2, Mi eia Ba celo2, E a Pe ez-Pampín3
and Juan J Gómez-Reino*3
Add ess: 1Rheuma ology Se ice, Hospi al Uni e si a io Vi gen Maca ena, Se illa, Spain, 2Rheuma ology Se ice, Hospi al Uni e si a io Vall
d'Heb on, Ba celona, Spain and 3Rheuma ology Se ice, Hospi al Clínico de San iago and Depa men o Medicine, USC, San iago, Spain
Email: Fede ico Na a o-Sa abia - ede ico.n[email p o ec ed]s; Dolo es Ruiz-Mon esinos - l uizmon [email protected];
Blanca He nandez - blancahc uz@ ele onica.ne ; Vic o ia Na a o-Compán - [email p o ec ed];
Sa a Ma sal - [email p o ec ed]heb on.ne ; Mi eia Ba celo - mba [email p o ec ed].ne ; E a Pe ez-Pampín - [email p o ec ed]; Juan J Gómez-
Reino* - juan.gomez- eino.ca no a@se gas.es
* Co esponding au ho
Abs ac
In oduc ion: No de ini i e da a a e a ailable ega ding he alue o swi ching o an al e na i e
TNF an agonis in heuma oid a h i is pa ien s who ail o espond o he i s one. The aim o his
s udy was o e alua e ea men esponse in a clinical se ing based on HAQ imp o emen and
EULAR esponse c i e ia in RA pa ien s who we e swi ched o a second o a hi d TNF an agonis
due o ailu e wi h he i s one.
Me hods: This was an obse a ional, p ospec i e s udy o a coho o 417 RA pa ien s ea ed
wi h TNF an agonis s in h ee uni e si y hospi als in Spain be ween Janua y 1999 and Decembe
2005. A da abase was c ea ed a he pa icipa ing cen es, wi h well-de ined ope a ional
ins uc ions. The main ou come a iables we e analyzed using pa ame ic o non-pa ame ic es s
depending on he le el o measu emen and dis ibu ion o each a iable.
Resul s: Mean (± SD) DAS-28 on s a ing he i s , second and hi d TNF an agonis was 5.9 (±
2.0), 5.1 (± 1.5) and 6.1 (± 1.1). A he end o ollow-up, i dec eased o 3.3 (± 1.6; Δ = -2.6; p >
0.0001), 4.2 (± 1.5; Δ = -1.1; p = 0.0001) and 5.4 (± 1.7; Δ = -0.7; p = 0.06). Fo he i s TNF
an agonis , DAS-28-based EULAR esponse le el was good in 42% and mode a e in 33% o pa ien s.
The second TNF an agonis yielded a good esponse in 20% and no esponse in 53% o pa ien s,
while he hi d one yielded a good esponse in 28% and no esponse in 72%. Mean baseline HAQ
on s a ing he i s , second and hi d TNF an agonis was 1.61, 1.52 and 1.87, espec i ely. A he
end o ollow-up, i dec eased o 1.12 (Δ = -0.49; p < 0.0001), 1.31 (Δ = -0.21, p = 0.004) and 1.75
(Δ = -0.12; p = 0.1), espec i ely. Six y ou pe cen o pa ien s had a clinically impo an
imp o emen in HAQ (de ined as ≥ -0.22) wi h he i s TNF an agonis and 46% wi h he second.
Conclusion: A clinically signi ican e ec size was seen in less han hal o RA pa ien s cycling o a
second TNF an agonis .
Published: 23 July 2009
BMC Musculoskele al Diso de s 2009, 10:91 doi:10.1186/1471-2474-10-91
Recei ed: 7 May 2009
Accep ed: 23 July 2009
This a icle is a ailable om: h p://www.biomedcen al.com/1471-2474/10/91
© 2009 Na a o-Sa abia e al; licensee BioMed Cen al L d.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0),
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
BMC Musculoskele al Diso de s 2009, 10:91 h p://www.biomedcen al.com/1471-2474/10/91
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Backg ound
T ea men wi h TNF an agonis s has imp o ed he ou -
come o heuma oid a h i is (RA) pa ien s [1]. In bo h
ea ly and es ablished RA, wo- hi ds o pa ien s achie e
meaning ul clinical esponses, ye one- hi d do no
espond. Addi ionally, a numbe o pa ien s ini ially
esponding de elop acqui ed d ug esis ance o g adual
d ug ailu e, and some ha e o discon inue he biologic
ea men due o ad e se e en s. O e all, he 3-yea e en-
ion a e o TNF an agonis s in RA is a ound 65% [2].
TNF an agonis s as a g oup ha e simila e icacy in RA,
al hough hei e ec i eness di e s in o he heuma ic dis-
eases. Mo eo e , case se ies and non andomized, open-
label obse a ional s udies in RA indica e ha some
pa ien s may ail o espond o one TNF inhibi o bu will
espond o ano he . This is pa ially suppo ed by da a
showing ha TNF an agonis s di e in hei pha macoki-
ne ics and mechanisms o ac ion [3]. Ne e heless, he e
a e no de ini i e da a ega ding he alue o swi ching
be ween TNF an agonis s. Ano he he apeu ic op ion is
o swi ch o a di e en class o biologic agen such as i ux-
imab, ocilizumab o aba acep [4-6].
The aim o his s udy was o e alua e in a clinical se ing
he clinical esponse based on e alua ion o HAQ and
EULAR esponse c i e ia in RA pa ien s wi h an insu i-
cien esponse o loss o e icacy o he i s TNF an ago-
nis who we e swi ched o a second o hi d one.
Me hods
This was an obse a ional, p ospec i e s udy o a coho o
417 RA pa ien s ea ed wi h TNF an agonis s in h ee uni-
e si y hospi als in Spain be ween Janua y 1999 and
Decembe 2005. A da abase was c ea ed a he pa icipa -
ing cen es, wi h well-de ined ope a ional ins uc ions.
Pa ien s who had pa icipa ed in clinical ials we e
excluded.
Pa ien s had been sys ema ically e alua ed a he ini ia-
ion o he apy and e e y h ee mon hs he ea e . Pa ien s
swi ching be ween TNF an agonis s o swi ching o i uxi-
mab we e e alua ed on s a ing he apy and e e y 3
mon hs he ea e . E alua ions included pain ul and
swollen join coun s, isual analogue scales o pain, glo-
bal heal h assessmen by he pa ien and he physician,
ESR, C- eac i e p o ein (CRP), Heal h Assessmen Ques-
ionnai e (HAQ) and DAS-28 sco e. DAS-28-based
EULAR esponse was es ima ed. Da a on he eason o
swi ching o a second TNF an agonis we e eco ded.
Desc ip i e s a is ics wi h cen al endency and dispe sion
measu es we e calcula ed. The main ou come a iables
we e analyzed using pa ame ic o non-pa ame ic es s
depending on he le el o measu emen and dis ibu ion
o each a iable. A p- alue < 0.05 ( wo ailed) was consid-
e ed signi ican . Su i al analysis was pe o med using
Kaplan-Meye cu es.
The s udy was conduc ed acco ding o good clinical p ac-
ice as applicable o epidemiological s udies, which
ensu es ha he design, implemen a ion and communica-
ion o da a a e eliable, and ha pa ien s' igh s, in eg i y
and da a con iden iali y a e p o ec ed. The s udy p o ocol
was app o ed by he E hics Commi ee o he Hospi al
Uni e si a io Vi gen Maca ena which conside ed ha
in o med consen was no equi ed due o he e ospec-
i e na u e o he analysis o anonymous da a.
Resul s
The ini ial TNF an agonis was in liximab (INF) in 238
cases (57%), e ane cep (ETA) in 141 (34%), and adali-
mumab (ADA) in 38 (9%). Eigh y- h ee pa ien s had
swi ched o a second TNF an agonis and 18 o a hi d TNF
an agonis . Mean pa ien ollow-up was 21.4 + 15.6
mon hs, and TNF exposu e was 443 pa ien -yea s o INF,
200.2 pa ien -yea s o ETA and 31.7 pa ien -yea s o
ADA. Swi ching in 48 cases (58%) was due o ine icacy,
in 24 cases (29%) o ad e se e en s, and in 11 cases
(13%) o o he easons, p ima ily he doc o 's o pa ien 's
decision.
Rele an clinical da a on he 417 pa ien s (82% women)
a e p esen ed in able 1. The mean age o pa ien s s a ing
hei i s TNF an agonis was 53 ± 13 yea s, and mean dis-
ease du a ion was 10.4 ± 8.2 yea s. Six y-eigh pe cen
we e RF posi i e and 74% p esen ed e osions. Th ee hun-
d ed nine y-six pa ien s (94%) ecei ed concomi an
DMARD; 324 me ho exa e (MTX), 33 le lunomide (LF)
and 21 an imala ials. Du ing ollow up, 263 pa ien s
(63%) con inued he i s TNF an agonis , 83 (20%)
swi ched o a second, and 18 (4%) o a hi d. Se en een
pe cen o pa ien s ecei ed no o he biologic a e discon-
inua ion. Fo y-six pa ien s ea ed wi h a second TNF
an agonis had swi ched om INF o ADA o ETA, 25 om
INF o ADA and 12 om ETA o ADA. Among pa ien s
ea ed wi h a hi d TNF an agonis , 12 had changed om
ETA o ADA, 5 om ADA o ETA, and 1 om ETA o INF.
Mean DAS-28 on s a ing he i s TNF an agonis was 5.9
± 2.0 and dec eased o 3.3 ± 1.6, a he end o ollow-up.
The imp o emen was s a is ically signi ican (Δ = -2.6; p
> 0.0001) o he whole g oup as well as o he h ee TNF
an agonis s conside ed independen ly. DAS-28 on s a -
ing he second TNF an agonis was 5.1 ± 1.5 and
dec eased o 4.2 ± 1.5 a he end o ollow-up (Δ = -1.1; p
= 0.0001). DAS-28 on s a ing he hi d TNF an agonis
was 6.1 ± 1.1 and dec eased o 5.4 ± 1.7 a he end o ol-
low-up (Δ = -0.7; p = 0.06). The esul s a e shown in
able 2.
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The DAS-28-based EULAR esponse le el o he i s TNF
an agonis was good in 42% o pa ien s and mode a e in
33%. Fo he second an i-TNF, good esponse was
achie ed in 20% o cases and 53% ailed o espond. Fo
he hi d TNF an agonis , 26% o cases had a good
esponse and 72% ailed o espond (Table 2). Response
o he second TNF an agonis did no di e signi ican ly
(p = 0.5) by he eason o swi ching (Table 3).
HAQ imp o ed signi ican ly (Table 2) wi h use o he i s
TNF an agonis , wi h a mean baseline sco e o 1.61 and
inal sco e o 1.12 (Δ = -0.49; p < 0.0001), wi h 64% o
pa ien s showing an imp o emen ≥ -0.22. Imp o emen
was no signi ican ly di e en wi h he h ee biologics. Fo
he second TNF an agonis , mean ini ial and inal HAQ
we e 1.52 and 1.31, espec i ely (Δ = -0.21, p < 0.004),
wi h 46% o pa ien s showing an imp o emen ≥ -0.22.
Fo he hi d TNF an agonis , HAQ sco es we e 1.87 and
1.75 a he ini ial and inal e alua ion, espec i ely (Δ = -
0.12; p = 0.1). The mean cumula i e change in HAQ om
p e- ea men wi h he i s TNF an agonis is depic ed in
igu e 1.
Re en ion a es wi h he i s TNF an agonis we e 80%,
62%, 53% and 34% a 12, 24, 36 and 60 mon hs, espec-
i ely. No signi ican di e ences we e ound among he
h ee d ugs (p = 0.1). The easons o discon inua ion
we e ine icacy (40%), ad e se e en s (40%) and o he
(20%). Re en ion a es wi h he second TNF an agonis
we e 70%, 60% and 47% a 12, 24 and 36 mon hs, espec-
i ely. Twen y- i e pa ien s discon inued he biologic,
mos commonly due o ine icacy (77%). Only 9 o he 18
pa ien s swi ching o a hi d TNF an agonis e ained he
biologic a 6 mon hs. Six s opped he biologic due o ine -
icacy.
Fi y- ou pa ien s had a se e e ad e se e en du ing ea -
men wi h he i s TNF an agonis . In usion eac ion was
he mos equen ad e se e en , occu ing in 16 pa ien s
ea ed wi h INF, ollowed by u ica ia o se e e skin ash
in 9 pa ien s, and uppe espi a o y ac in ec ion in 8.
O he less equen ad e se e en s we e conges i e hea
ailu e, ube culosis, he pes zos e in ec ion, acu e panc e-
a i is, cu aneous asculi is and lupus-like synd ome.
Se en pa ien s had se e e ad e se e en s while ea ed
wi h he second TNF an agonis (Table 4).
Discussion
In he p esen s udy we desc ibe ele an ou comes in clin-
ical p ac ice in RA pa ien s ailing o espond o one TNF
an agonis and swi ching o ano he , in compa ison wi h
RA pa ien s who e ain he i s an agonis . Ou da a show
ha a numbe o pa ien s swi ching be ween TNF an ago-
nis s may a ain a signi ican esponse, ye a la ge p opo -
Table 1: Cha ac e is ics o pa ien s swi ching be ween TNF an agonis s
1s TNF an agonis (417) 2nd TNF an agonis (83) 3 d TNF an agonis (18)
Age, yea s (SD) 53 ± 13 52 ± 12 44 ± 11
Gende (F) 342 (82%) 68(82%) 17(94%)
Disease du a ion yea s (SD) 10.4 (± 8,2) 10 (± 8) 11(± 8)
RF posi i e, % 68% 69% 61%
Radiog aphic e osions, % 74% 79% 94%
Concomi an DMARD, % 94% 94% 100%
Me ho exa e 78% 71% 50%
Le lunomide 8% 2% 17%
An imala ial 5% 4% 5%
O al glucoco icoids, % 83% 83% 51%
Adalimumab, n 38 36 12
E ane cep , n 141 46 5
In liximab, n 238 1 1
Table 2: Imp o emen in DAS 28 and HAQ, and DAS-28-based EULAR esponse in pa ien s swi ching be ween TNF an agonis s
1s TNF an agonis 2nd TNF an agonis 3 d TNF an agonis
Ini ial Final Δp Ini ial Final Δp Ini ial Final ΔP
DAS-28 5.9 3.3 -2.6 <0.0001 5.1 4.2 -1.1 0.0001 6.1 5.4 -0.7 0.06
HAQ 1.61 1.12 -0.49 <0.0001 1.52 1.31 -0.21 <0.004 1.87 1.75 -0.12 0.1
Good (%)* 174(42) 17(20) 5(28)
Mode a e (%)* 138(33) 20(27)
No esponse (%)* 105(25) 44(53) 13(72)
* DAS-28-based EULAR esponse
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ion o pa ien s ha e ma ginal o no clinical
imp o emen . Imp o emen is gene ally negligible in
pa ien s swi ching o a hi d biologic. In e es ingly,
pa ien s swi ching o a hi d TNF an agonis we e younge ,
mo e equen ly emale, and had a highe p e alence o
e osions despi e he ac ha disease du a ion was simila
o he o he pa ien s. This g oup p obably ep esen s a
subse o pa ien s wi h mo e se e e disease which is esis -
an o hese biologics.
Up o Sep embe 2008, he e we e 35 epo s in he li e -
a u e [7-42] on swi ching be ween TNF an agonis s in RA
pa ien s who expe ience ea men ailu e. Twen y epo s
we e based on obse a ional s udies, 10 on case se ies and
6 on p ospec i e coho s om biologic egis ies. Addi-
ionally he e we e 2 andomized clinical ials [8,11]: 1
double-blind and 1 open-label s udy. The wo clinical i-
als demons a e he e icacy o swi ching be ween TNF
an agonis s. On he whole, he nume ous design limi a-
ions o he o he s udies limi hei alue. Ne e heless,
he as majo i y o hem epo on he a ou able e icacy
o swi ching, ye in o ma ion on he e ec size is la gely
un epo ed.
Mos pa ien s included in p e ious publica ions we e
women (83%, ange: 60–100), wi h an a e age age o 52
yea s ( ange: 32–68), and a disease du a ion o 12 yea s
( ange: 3–27). When epo ed a baseline, mean DAS was
5.6 ( ange: 2.4–6.8), and mean HAQ 1.7 ( ange: 1.5–1.9).
This baseline in o ma ion is no di e en om wha was
ound in ou s udy. O no e, ew publica ions epo on
DAS-28 e ec size, DAS-based EULAR esponse and HAQ
imp o emen in pa ien s swi ching be ween TNF an ago-
nis s in compa ison wi h pa ien s who e ain he i s
an agonis . A alue o -0.22 in HAQ is conside ed he
minimum clinically impo an di e ence (MCID) in s ud-
ies o esponsi eness [43]. The size o imp o emen wi h
he i s TNF an agonis (-0.40) is wi hin he ange o wha
has been epo ed in clinical ials [44-46]. Two- hi ds o
pa ien s ea ed wi h he i s and less han hal o hose
ea ed wi h he second TNF an agonis had a MCID in
HAQ. Despi e long-s anding disease, HAQ imp o emen
was pa allel o DAS-28 imp o emen , a esul ha was
unan icipa ed based on p e ious da a [47].
Th ee s udies [14,15,20] ha e desc ibed e en ion a es o
a second TNF an agonis as a su oga e o e ec i eness.
O e all, he p obabili y o e aining a second TNF an ago-
nis was lowe han e aining he i s one. The p obabili y
was in luenced by he eason o d ug eplacemen , i.e.
d ug ailu e o ad e se e en . In e es ingly, he easons o
s opping a second d ug we e ela ed o he easons o
s opping he i s d ug [15]. Al hough he e en ion a e o
a d ug can be aken as a easonable indica o o i s e ec-
i eness, pa ame e s o he han e icacy and sa e y, such as
co-mo bidi y, co-medica ions, cos s, a ailabili y o o he
he apies, pa ien s' and physicians' expec a ions, and
adhe ence o ea men could in luence d ug su i al. In
ou s udy, e en ion a es o he second and hi d TNF
an agonis s we e wi hin he bounda ies o wha o he
au ho s ha e epo ed, sugges ing ha hese a es a e con-
sis en ly ound in clinical p ac ice. He ein, we show ha
lack o esponse o a i s TNF an agonis does no p edic
he esponse o a second one, ye he e icacy o a second
TNF an agonis is in e io o ha o he i s .
Conclusion
A signi ican ea men e ec size wi h a second TNF
an agonis in RA pa ien s ailing o espond o he i s one
is limi ed o less han hal o hose ea ed. Fu he mo e,
RA pa ien s who a e e ac o y o TNF-an agonis ea -
men ha e a poo e esponse o i uximab, aba acep and
ocilizumab han pa ien s who a e nai e o biological
d ugs. E idence ha he e icacy o cycling be ween TNF
an agonis s is simila o supe io o swi ching o he new
biologics is la gely missing. The esul s epo ed by o he
au ho s [48] as well as hose o ou own s udy sugges ha
his may no be he case.
Table 3: DAS-28-based EULAR esponse in pa ien s swi ching o
a second TNF an agonis , by eason o swi ching
Ine icacy
N (%)
Ad e se e en s
N (%)
O he easons
N (%)
Good 10 (20) 6 (25) 1 (10)
Mode a e 12 (25) 8 (30) 2 (18)
No esponse 26 (55) 10 (45) 8 (72)
Mean cumula i e change in HAQ om s a ing he apy in pa ien s wi h heuma oid a h i is ollowing cycling be ween TNF an agonis s.Figu e 1
Mean cumula i e change in HAQ om s a ing he -
apy in pa ien s wi h heuma oid a h i is ollowing
cycling be ween TNF an agonis s.
3 d TNF
an agonis
2nd TNF
an agonis
1s TNF
an agonis
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Abb e ia ions
ADA: Adalimumab; DAS: Disease Ac i i y Sco e; ETA:
E ane cep ; EULAR: Eu opean League Agains Rheuma-
ism; HAQ: Heal h Assessmen Ques ionnai e; INF: In lix-
imab; LF: Le lunomide; MCID: Minimum Clinically
Impo an Di e ence; MTX: Me ho exa e; RA: Rheuma-
oid A h i is; TNF: Tumo Nec osis Fac o .
Compe ing in e es s
DRM, BH, VNC, SM and MB decla e ha hey ha e no
compe ing in e es s. FNS and JJGR ha e pa icipa ed in
Ad iso y Boa ds and ecei ed lec u e ees om Abbo ,
B is ol-Maye -Squib, Roche, Sche ing-Plough and Wye h.
Au ho s' con ibu ions
FNS and JJGR concei ed, designed and coo dina ed he
s udy, and p epa ed he d a o he manusc ip . DRM,
VNC, SM and MB collec ed he da a and e iewed he da a
analyses. BH pe o med he s a is ical analysis and con-
ibu ed o he design o he s udy. All au ho s ead and
app o ed he inal manusc ip .
Acknowledgemen s
The s udy was pa ially unded by a g an o BMS, Spain, and by RETICS P o-
g am, RD08/0075 (RIER) om he Ins i u o de Salud Ca los III (ISCIII),
wi hin he VI PN de I+D+I 2008–2011.
Re e ences
1. Keys one EC: S a egies o con ol disease in heuma oid
a h i is wi h umo nec osis ac o an agonis s–an oppo u-
ni y o imp o e ou comes. Na u e Clin P ac Rheuma ol 2006,
2:594-601.
2. Ca mona L, Gómez-Reino JJ, BIOBADASER G oup: Su i al o
TNF an agonis s in spondyla h i is is be e han in heu-
ma oid a h i is. Da a om he Spanish egis y BIOBA-
DASER. A h i is Res The 2006, 8:R72.
3. T acey D, Kla eskog L, Sasso EH, Sal eld JG, Tak PP: Tumo nec o-
sis ac o an agonis mechanisms o ac ion: a comp ehensi e
e iew. Pha macol The 2008, 117:244-279.
4. Cohen SB, Eme y P, G eenwald MW, Dougados M, Fu ie RA, Gen-
o ese MC, Keys one EC, Lo eless JE, Bu mes e GR, C a e s MW,
Hessey EW, Shaw T, To o i is MC: Ri uximab o heuma oid
a h i is e ac o y o an i- umo nec osis ac o he apy:
Resul s o a mul icen e , andomized, double-blind, placebo-
con olled, Phase III ial e alua ing p ima y e icacy and
sa e y a wen y- ou weeks. A h i is Rheum 2006, 54:2793-2806.
5. Eme y P, Keys one E, Tony HP, Can ag el A, an Vollenho en R,
Sanchez A, Alecock E, Lee J, K eme J: IL-6 ecep o inhibi ion
wi h ocilizumab imp o es ea men ou comes in pa ien s
wi h heuma oid a h i is e ac o y o an i- umou nec osis
ac o biologicals: esul s om a 24-week mul icen e an-
domised placebo-con olled ial. Ann Rheum Dis 2008,
67:1516-23.
6. Geno ese MC, Schi M, Luggen M, Becke JC, A anda R, Teng J, Li T,
Schmidely N, Le Ba s M, Dougados M: E icacy and sa e y o he
selec i e co-s imula ion modula o aba acep ollowing 2
yea s o ea men in pa ien s wi h heuma oid a h i is and
an inadequa e esponse o an i- umou nec osis ac o he -
apy. Ann Rheum Dis 2008, 67:547-54.
7. Hy ich KL, Lun M, Dixon WG, Wa son KD, Symmons DP, BSR Bio-
logics Regis e : E ec s o swi ching be ween an i-TNF he a-
pies on HAQ esponse in pa ien s who do no espond o
hei i s an i-TNF d ug. Rheuma ology (Ox o d) 2008, 47:1000-5.
8. Smolen J, Kay J, Doyle MK, Landewe R, Ma eson EL, Wollenhaup J,
Gaylis N, Mu phy F, Neal J, Zamani O, Zhou Y, Vis ana han S, Hsia
EC, Rahman MU: Golimumab, a new human an i-TNF-alpha
monoclonal an ibody, subcu aneously adminis e ed e e y 4
weeks in pa ien s wi h ac i e heuma oid a h i is who we e
p e iously ea ed wi h an i-TNF-alpha agen (s): Resul s o
he andomized double-blind, placebo-c (sic) [abs ac ]. Ann
Rheum Dis 2008, 67(suppl II):50.
9. Ka lsson JA, K is ensen LE, Kape ano ic MC, Gul e A, Saxne T,
Gebo ek P: T ea men esponse o a second o hi d TNF-
inhibi o in RA: esul s om he Sou h Swedish A h i is
T ea men G oup Regis e . Rheuma ology (Ox o d) 2008,
47:507-513.
10. Blom M, Kie i W, F ansen J, Kupe IH, Laa M an de , de Rooj D,
de Gend C, Jansen TL: E ec i eness o a swi ch o a second
an i-TNF-α in p ima y non esponde s, seconda y non e-
sponde s and ailu e due o ad e se e en s. [abs ac ]. A h i-
is Rheum 2007, 56(suppl):S165.
11. Fu s DE, Gaylis N, B ay V, Olech E, Yocum D, Ri e J, Weisman M,
Wallace DJ, C ues J, Khanna D, Eckel G, Yeilding N, Callega i P, Vis-
ana han S, Rojas J, Hegedus R, Geo ge L, Mamun K, Gilme K, T oum
O: Open-label, pilo p o ocol o pa ien s wi h heuma oid
a h i is who swi ch o in liximab a e an incomple e
esponse o e ane cep : The OPPOSITE s udy. Ann Rheum Dis
2007, 66:893-9.
12. Finckh A, Ciu ea A, B ulha L, Kybu z D, Mölle B, Dehle S, Re az
S, Dudle J, Gabay C: An i- umo nec osis ac o alpha swi ch-
ing in heuma oid a h i is and ju enile ch onic a h i is.
A h i is Rheum 2004, 51:301-2.
13. Buch MH, Bingham SJ, Beja ano V, B ye D, Whi e J, Reece R, Quinn
M, Eme y P: The apy o pa ien s wi h heuma oid a h i is:
Table 4: Se ious ad e se e en s occu ing in pa ien s swi ching be ween TNF an agonis s
1s TNF an agonis
(n = 417)
2nd TNF an agonis
(n = 83)
3 d TNF an agonis
(n = 18)
Uppe espi a o y in ec ions 8 1
U ica ia 3
Sys emic lupus e y hema osus 2
He pes zos e 2
Rash 3 1 1
Tube culosis 2 1
In usion eac ions 16 1
Ca diac insu iciency 3
Acu e panc ea i is 2
Cu aneous asculi is 2
E y hema 3
In ec ious a h i is 2
Leukopenia 1
BMC Musculoskele al Diso de s 2009, 10:91 h p://www.biomedcen al.com/1471-2474/10/91
Page 6 o 7
(page numbe no o ci a ion pu poses)
ou come o in liximab ailu es swi ched o e ane cep . A h i-
is Rheum 2007, 57:448-53.
14. Con i F, Cecca elli F, Ma occhi E, Mag ini L, Romana Spinelli F, Spa-
da o A, Sc i o R, Valesini G: Swi ching TNF{alpha} an agonis s
in pa ien s wi h ankylosing spondyli is and pso ia ic a h i is:
an obse a ional s udy o e a i e-yea pe iod. Ann Rheum Dis
2007, 66:1393-7.
15. Hja dem E, Os e gaa d M, Pødenphan J, Ta p U, Ande sen LS, Bing
J, Peen E, Lindegaa d HM, Ringsdal VS, Rødgaa d A, Skø J, Hansen A,
Mogensen HH, Unke sko J, He land ML: Do heuma oid a h i is
pa ien s in clinical p ac ice bene i om swi ching om in -
liximab o a second umo nec osis ac o alpha inhibi o ?
Ann Rheum Dis 2007, 66:1184-1189.
16. Hy ich KL, Lun M, Wa son KD, Symmons DP, Silman AJ: Ou comes
a e swi ching om one an i- umo nec osis ac o alpha
agen o a second an i- umo nec osis ac o alpha agen in
pa ien s wi h heuma oid a h i is: esul s om a la ge UK
na ional coho s udy. A h i is Rheum 2007, 56:13-20.
17. Iannone F, T o a F, Mon ecucco C, Giacomelli R, Galeazzi M,
Ma ucci-Ce inic M, Fe i C, Cu olo M, Ma ia Bamba a L, T iolo G,
Fe accioli G, Valen ini G, Lapadula G, GISEA (G uppo I aliano pe lo
S udio delle Ea ly A h i is): E ane cep main ains he clinical
bene i achie ed by in liximab in pa ien s wi h heuma oid
a h i is who discon inued in liximab because o side e ec s.
Ann Rheum Dis 2007, 66:249-252.
18. A zeni F, Sa zi-Pu ini P, An i alle M, Tu iel M, Ca abba M: Adali-
mumab in se e e heuma oid a h i is a e ailu e o wo
an i-TNF agen s: a p ospec i e 1-yea ollow-up s udy o 15
pa ien s. Ann Rheum Dis 2006, 65(Suppl II):630.
19. Bomba die i S, McKenna F, D osos AA, Michel BA, Ha z D, Oeze
U: E icacy and sa e y o adalimumab (HUMIRA®) in 899
pa ien s wi h heuma oid a h i is who p e iously ailed
e ane ce p and/o in liximab in clinical p ac ice [abs ac ].
Ann Rheum Dis 2006, 65(Suppl II):178.
20. Can ini F, Niccoli L, Benucci M, Chindamo D, Nannini C, Oli ie i I,
Padula A, Sal a ini C: Swi ching om in liximab o once-weekly
adminis a ion o 50 mg e ane cep in esis an o in ole an
pa ien s wi h ankylosing spondyli is: esul s o a i y- ou -
week s udy. A h i is Rheum 2006, 55:812-6.
21. Gomez-Reino JJ, Ca mona L: Swi ching TNF an agonis s in
pa ien s wi h ch onic a h i is: an obse a ional s udy o 488
pa ien s o e a ou -yea pe iod. A h i is Res The 2006, 8:R29.
Epub 2006 Jan 6
22. Nikas SN, Voulga i PV, Alamanos Y, Papadopoulos CG, Vene sanop-
oulou AI, Geo giadis AN, D osos AA: E icacy and sa e y o
swi ching om in liximab o adalimumab: a compa a i e
con olled s udy. Ann Rheum Dis 2006, 65:257-260.
23. Solau-Ge ais E, Laxenai e N, Co e B, Dubucquoi S, Duquesnoy B,
Flipo RM: Lack o e icacy o a hi d umou nec osis ac o
alpha an agonis a e ailu e o a soluble ecep o and a
monoclonal an ibody. Rheuma ology (Ox o d) 2006, 45:1121-1124.
24. Bingham CO, Ha aoui PB, Rigby WFC, Mon al o-Lugo V, Chon T:
Disease cha ac e is ics o pa ien s wi h heuma oid a h i is
ha ailed o espond o in liximab and he esponse o
e ane cep he apy: p elimina y da a om EMBARK s udy.
Ann Rheum Dis 2005, 64(Suppl III):172.
25. Bomba die i S, Ruiz AA, Fa dellone P, Geusens P, McKenna F, Unne-
b ink K, Oeze U, Ka y S, Kuppe H, Bu mes e GR: Resea ch in
Ac i e Rheuma oid A h i is (ReAc ) S udy G oup E ec i e-
ness o adalimumab o heuma oid a h i is in pa ien s wi h
a his o y o TNF-an agonis he apy in clinical p ac ice. Rheu-
ma ology (Ox o d) 2007, 46:1191-9.
26. Bu mes e GR, Ma ie e X, Mon ecucco C, Mon eagudo-Sáez I,
Malaise M, Tziou as AG, Bijlsma JW, Unneb ink K, Ka y S, Kuppe H:
Adalimumab alone and in combina ion wi h disease-modi y-
ing an i heuma ic d ugs o he ea men o heuma oid
a h i is in clinical p ac ice: he Resea ch in Ac i e Rheuma-
oid A h i is (ReAc ) ial. Ann Rheum Dis 2007, 66:732-9.
27. Can ini F, Niccoli L, Po ciello G: Swi ching om in liximab o
adalimumab o e ane cep 50 Mg/once weekly in esis an o
in ole an pa ien s wi h heuma oid a h i is: 24-week
esul s. A h i is Rheum 2005, 52(suppl):S560.
28. Cohen G, Cou oisie N, Cohen JD, Zal ni S, Sany J, Combe B: The
e iciency o swi ching om in liximab o e ane cep and
ice- e sa in pa ien s wi h heuma oid a h i is. Clin Exp Rheu-
ma ol 2005, 23:795-800.
29. Delaunay C, Fa enq V, Ma ini-Po ugal A, Cohen JD, Che alie X,
Claudepie e P: In liximab o e ane cep swi ch in pa ien s
wi h spondyloa h opa hies and pso ia ic a h i is: p elimi-
na y da a. J Rheuma ol 2005, 32:2183-2185.
30. Bijl AE Van de , B eed eld FC, An oni C, Kalden JR, Ka y S, Bu m-
es e GR, Unneb ink K, Kuppe H: Adalimumab (HUMIRA®) is
e ec i e in ea ing pa ien s wi h heuma oid a h i is who
p e iously ailed in liximab ea men . Ann Rheum Dis 2005,
64(Suppl III):428.
31. Wick MC, E nes am S, Lindblad S, B a J, Kla eskog L, an Vollen-
ho en RF: Adalimumab (Humi a) es o es clinical esponse in
pa ien s wi h seconda y loss o e icacy om in liximab
(Remicade) o e ane cep (Enb el): esul s om he STURE
egis y a Ka olinska Uni e si y Hospi al. Scand J Rheuma ol
2005, 34:353-358.
32. Ka sicas MM, Russo RA: Use o in liximab in pa ien s wi h sys-
emic ju enile idiopa hic a h i is e ac o y o e ane cep .
Clin Exp Rheuma ol 2005, 23:545-548.
33. Keys one EC, Pe uque JL, Lidman RW: Swi ching an i-TNF
he apy: eal-wo ld ou come o pa ien s wi h heuma oid
a h i is who ailed ei he in liximab o e ane cep ea -
men and swi ched o ano he TNF inhibi o [abs ac ].
A h i is Rheum 2004, 51(Suppl):S990.
34. Fa alli EG, A eghini M, A noldi C, Panni B, Ma chesoni A, Tosi S,
Pon ikaki I: An i- umo nec osis ac o alpha swi ching in
heuma oid a h i is and ju enile ch onic a h i is. A h i is
Rheum 2004, 51:301-302.
35. Hansen KE, Hildeb and JP, Geno ese MC, Cush JJ, Pa el S, Cooley
DA, Cohen SB, Gangnon RE, Schi MH: The e icacy o swi ching
om e ane cep o in liximab in pa ien s wi h heuma oid
a h i is. J Rheuma ol 2004, 31:1098-1102.
36. Ha aoui B, Keys one EC, Tho ne JC, Pope JE, Chen I, Asa e CG, Le
JA: Clinical ou comes o pa ien s wi h heuma oid a h i is
a e swi ching om in liximab o e ane cep . J Rheuma ol
2004, 31:2356-2359.
37. Sanma i R, Gomez-Pue a JA, Rod iguez-C os JR, Albaladejo C,
Munoz-Gomez J, Cane e JD: E ane cep in heuma oid a h i is
pa ien s wi h a poo he apeu ic esponse o in liximab. Med
Clin (Ba c) 2004, 122:321-324.
38. Yazici Y, E kan D: Do e ane cep -nai e pa ien s wi h heuma-
oid a h i is espond be e o in liximab han pa ien s o
whom e ane cep has ailed? Ann Rheum Dis 2004, 63:607-608.
39. Ang HT, Hel go S: Do he clinical esponses and complica-
ions ollowing e ane cep o in liximab he apy p edic sim-
ila ou comes wi h he o he umo nec osis ac o -alpha
an agonis s in pa ien s wi h heuma oid a h i is? J Rheuma ol
2003, 30:2315-2318.
40. an Vollenho en R, Ha ju A, B annema k S, Kla eskog L: T ea men
wi h in liximab (Remicade) when e ane cep (Enb el) has
ailed o ice e sa: da a om he STURE egis y showing
ha swi ching umou nec osis ac o alpha blocke s can
make sense. Ann Rheum Dis 2003, 62:1195-1198.
41. B ocq O, Plubel Y, B euil V, G iso C, Flo y P, Mousnie A, Eulle -Zie-
gle L: E ane cep –in liximab swi ch in heuma oid a h i is
14 ou o 131 pa ien s ea ed wi h an i TNFalpha. P esse Med
2002, 31:1836-1839.
42. She gy W, Phillips RM, Hun RE, He nandez J: Expe ience wi h
comme cial emicade (in liximab) a a la ge communi y-
based heuma ology p ac ice [abs ac ]. A h i is Rheum 2001,
44(Suppl):S81.
43. Bea on DE, Bomba die C, Ka z JN, W igh JG, Wells G, Boe s M,
S and V, Shea B: Looking o impo an change/di e ences in
s udies o esponsi eness. OMERACT MCID Wo king
G oup. J Rheuma ol 2001, 28:400-5.
44. Lipsky PE, Heijde DM an de , S Clai EW, Fu s DE, B eed eld FC,
Kalden JR, Smolen JS, Weisman M, Eme y P, Feldmann M, Ha iman
GR, Maini RN: In liximab and me ho exa e in he ea men
o heuma oid a h i is. N Engl J Med 2000, 43:1594-602.
45. Weinbla ME, Keys one EC, Fu s DE, Mo eland LW, Weisman MH,
Bi ba a CA, Teoh LA, Fischko SA, Cha ash EK: Adalimumab, a
ully human an i- umo nec osis ac o alpha monoclonal
an ibody, o he ea men o heuma oid a h i is in
pa ien s aking concomi an me ho exa e: he ARMADA
ial. A h i is Rheum 2003, 48:35-45.
46. Weinbla ME, K eme JM, Bankhu s AD, Bulpi KJ, Fleischmann RM,
Fox RI, Jackson CG, Lange M, Bu ge DJ: A ial o e ane cep , a
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ecombinan umo nec osis ac o ecep o : Fc usion p o-
ein, in pa ien s wi h heuma oid a h i is ecei ing me h-
o exa e. N Engl J Med 1999, 340:253-9.
47. Ale aha D, Wa d MM: Du a ion o heuma oid a h i is in lu-
ences he deg ee o unc ional imp o emen in clinical ials.
Ann Rheum Dis 2006, 65:227-33.
48. Finckh A, Ciu ea A, B ulha L, Kybu z D, Mölle B, Dehle S, Re az
S, Dudle J, Gabay C: Physicians o he Swiss Clinical Quali y
Managemen P og am o Rheuma oid A h i is: B cell
deple ion may be mo e e ec i e han swi ching o an al e -
na i e an i- umo nec osis ac o agen in heuma oid
a h i is pa ien s wi h inadequa e esponse o an i- umo
nec osis ac o agen s. A h i is Rheum 2007, 56:1417-23.
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