TAP CHI NGHIEN CU'U Y HQC •
DANH GIA KET QUADI^U TRj CUATOCILI2UMAB (ACTEMRA) a BENH NHAN VIEM KHQP DANG THAP
Tr^n Thj Minh Hoa Khoa Ca xwong khap. B$nh vi$n Bach Mai Nghien c&u nhim budc dau danh gia hieu qua. tinh an toan cua Tocilizumab (Artemra) sau 12 tuin diiu tn benh nhan viem khop dang thip Kit qua cho thay sw cai thien co y nghTa thdng ke vdi p < 0,01 ve lam sang va tiin then benh d ca 10 benh nhan viem khdp dang thap sau 12 tuin diiu tn bing Artemra nhw thang diim dau VAS (giam t& 7,7 xudng 1,9). chl sd ho?t ddng DAS28-CRP (giam t& 5.45 xudng 2.1) vacac chi sd viem khac (tdc dd mau lang, CRP) diu giam cd y nghia thdng k§ (p < 0.01) Khdng cd tac dijng phu ciia thudc duac ghi nhan trong thdi gian nghien cuv. Kit luan: Tocilizumab (Artemra) cd hieu qua diiu tri b$nh viem khdp d^ng thip
Ti> khioa: viem kho'p dang t h i p , Tocilizumab (Artemra)
I. DAT
V A N D ^Tocilizumab(Artemra) la mdt khang the dan ddng yc e h i y i u td viem interieukin-6 (IL- 6) dyae ca quan quan ly thyc pham va thude Hoa Ky (FDA) edng nhan chi dmh d i i u tri benh viem khdp dang t h i p , vigm khdp t h i i u men t y phat [1] lnterleukin-6 (IL-6) la mdt trong nhOng eytokin ddng vai trd quan trong trong qua trinh benh smh cua benh vidm khdp dang t h i p (VKDT) (2, 3] D i i u tri benh viem khdp dang t h i p e i n phai phoi hap nhiiu bien phap d i i u tri n h i m mue dich han c h i s y ton thyang sun khdp va mang hoat dieh Theo Fleishmann R [4] lnterleukin-6 giCF vai trd quan trong trong qua trinh viem vi IL-6 la san pham cua cac t i bao khac nhau ed vai trd hoat hod va kich thieh nguyen bao sai tang sinh tao ra cac e h l t tidu protein (matrix metallopro- teinase) va IL-6 cdn cd vai trd kich thich lam tang cdc cytokin va eae c h i t t i i n viem khac gay nen tinh trang vigm man tinh trong cac bgnh t y m i l n dich, dac bigt la benh vigm khdp dang t h i p . Vi vay thudc tocilizumab (Artemra) LFC c h i IL-6 se lam giam ndng dd cytokin IL-6, LFo c h i qua trinh vigm va kiem soat sy tien tnen cua benh vigm khap dang t h i p [2, 5],
Hien nay tocilizumab (Artemra) d y a c danh gia la mdt trong nhdng lidu phap d i i u tn, smh hoe tdt, higu qua va an toan trong d i l u tri benh vigm khdp dang t h i p dae biet la cac trydng hap benh nhan khdng dap LFng vdi cac phyang phap d i i u tri t r y d c day da ap dung, k i ca cac trydng hap d i i u tn vdi thudc cd tac dung smh hoc khac [2, ^, 5], tuy nhidn do Ac- temra la mdt loai thude mdi, gia thanh thude cdn cao va phai truyen tTnh maeh nen viee s y dung d i i u tn thudc nay cho benh nhan viem khdp dang t h i p d nyde ta cdn han c h i , Chung tdi t l i n hanh d i tai nay n h i m muc dich bydc d i u danh gia higu qua va an toan sau 12 t u i n d i i u tn tocilizumab (Artemra) cua 10 benh nhan vigm khdp dang t h i p d y a c e h l n doan va d i i u tri tai khoa Khdp bgnh vign Bach Mai tiF thang 9 nam 2011 d i n thang 1 nam 2012
II. D 6 | TU'O'NG VA PHLPONG PHAP
1. 061 tu'O'ng
10 bgnh nhan d y a c chan doan vigm khdp dang t h i p theo tigu c h u i n cua Hdi T h i p khdp hoe Hoa ky (1987) d i i u tn tai Khdp benh vidn Bach Mai trong thai gian tiF thang 9/2011 d i n thang 1/2012- Tieu chuan loai try; benh nhan
viem khdp dang t h i p cd ph6i hap vdi eac ton thyang lao, nhiim khuIn nang, nhilm n i m . bdnh ae tinh Cae benh nhan cd cac xdt nghigm dyang tinh Mantoux, HIV, HbsAg deu loai khdi nghign ciju nay,
2. Phuxj-ng phap: md ta c l t ngang, tiin cyu cd can thiep dieu tn: bgnh nhan d i u dyae kham lam sang, xac dmh thang diem dau VAS, sd khdp syng, khdp dau, thdi gian cyng khdp buoi sang, chi s6 DAS 28-CRP, cac xet nghidm huyit hoc, sinh hoa, y i u to dang t h i p (RF).. d i u dyac danh gia tai cac thdi d i i m trudc khi d i i u tn (TO), sau 4 tuin (Tl), 8 tuan (T2) va 12 t u i n (T3) d i i u tri Chup tim phoi kiem tra tai 2 thdi diem TO va T3 Lieu trinh d i i u trj truyin tTnh mach thudc Actemra mdi thang 1 l l n vdi lieu 8mg/kg/4 t u i n
III. K i T QUA
1. Dac digm benh nhan nghien cu>u
TAP CHI NGHIEN C t f U Y HOC Nhdm benh nhan nghien CLFU ed tuoi trung binh la 36,8 +_10,4 tuoi (tCF 22 tuoi d i n 55 tuoi), trong dd benh nhan n y ehiim da s i 8/10 benh nhan (80%), thdi gian m i c bgnh trung binh la 4,8 nam (tCF 1 nam d i n 9 nSm) Cd 6/10 benh nhan (60%) ed tinh trang phu thude eorticoid Cdc benh nhan d i u da d y a c d i i u tn it n h l t b i n g mdt loai thuoc ea ban nhy cloro- quin (90%), methotrexat (70%), salaropynn (30%), medrol (60%) vdi thai gian si> dung cae thudc d i i u tri c a ban trung binh la 2,3 ± 1,7 nam
e.. Hi€u qua cua Tocilizumab (Artemra) sau 12 t u i n digu trj 10 benh nhan VKDT tai cac thd'i d i i m TO, T 1 , T2 va T3
2 1 Cai thi§n thang diim dau va thd-i gian cimg kh&p budi sang a cac thai diim sau 4 tuin (Tl), 8 tuin (T2), vd 12 tuin (T3) truyin Unh mach Actemra
TO T l T 2 1 3
H i n h 1a. T h a n g d i i m V A S H i n h l b . Thd'i g i a n cipng k h d p b u d i s a n g Thang d i i m dau VAS d y a c eai thien 7,7 diem d thdi d i i m TO va 1,9 diem d thdi d i i m T3 (p < 0,01). Thdl gian c y n g khdp buoi sdng d y a c cai thidn rut n g i n d i n tCF 70,5 phut (TO) xudng 33,8 phut {T3) vdi p < 0,01
2.2 Cai thiin c^c cht so kh&p swng, kh6p dau vd DAS 28-CRP a cac thai diim sau 4 tuin (Tl), sau 8 tuin (T2), va sau 12 tuin (T3) truyin Actemra
Cd s y cai thien v i sd khdp dau, sd khdp syng va chi so DAS 28-CRP So khdp syng, khdp dau deu giam sau cdiC thdi diem nghien edu vdi p < 0,01, t y a n g t y ehi so hoat ddng benh DAS 28-CRP cung giam cd y nghTa t h i n g ke vdi p < 0,01 trong qua trinh dieu tri 5,45 (TO), 3,45 ( T l ) , 2,65(T2), va2,1(T3)
TCNCYH 80 (3)-2012
TAP CHI NGHIEN CU'U Y HQC •
_ n
— -
D So kho'p dau
• Sd kho'p su'ng
1 III
X x:
TO T2 T3 T4 Hinh 2a. S6 kho'p dau, khd-p su'ng
TO Tl T2 T3
Hinh 2b. Chi s6 hoat dong benh DAS 28-CRP 2 3 Cai thidn cac chl s6 can lam sang cua binh nhan a c6c thai diem sau 4 tudn (T1), sau 8 tuin (T2), va sau 12 tuin (T3) truyin Actemra
Bang 1 . Cac chi s6 can lam sang cua nhom nghien CLFU tai cac thd'i d i i m nghien cu'u
Cac chi so can lam sang Toe (56 mau lang gio 1 (mm) Nflng afl CRP (mg/dl) Y i u to dang t h i p RF (lU/l) Nflng dfl hemoglobin (g/l)
TO 74,6 4,5 158,2 102,7
T1 42,5
3,1 122,4 110,3
T2 30,6
2,5 87,5 115,6
T3 18,4
1,2 55,2 120,8
P
<0,01
<0,01
<0,01
>0,01
Cd sy cai thien cua cac ehi sd can iam sang nhy toe dd mau lang, CRP huyet thanh, yeu to dang t h i p RF d i u giam sau cac thdi d i i m d i i u tn vdi s y khac biet cd y nghTa t h i n g kg p < 0,01 Ndng do hemoglobin bgnh nhan cd tang len sau 12 t u i n d i i u tri tuy nhien khdng cd sy khdc bigtcd y nghTa t h i n g kg (p > 0,01)
3.3 Bifac dau nhan xdf tinh an toan cua thudc Tocilizumab (actemra!) sau 12 tuin diiu tnalO bdnh nhan viem kh&p dang thip
Ca 10 benh nhan d i u khdng b i i u hien b i t CLF mdt phan yng khdng mong mudn nao cua thudc ngay sau truyen tTnh mach Actemra cOng nhy trong s u i t qud trinh 12 t u i n theo ddi d i i u tn, Cac benh nhan cijng khdng ed eae b l i u hien nhiem k h u I n d y d n g hd h i p trdn hoac cac n h i l m khuan khac Mat khac cac ehi sd smh hda v i chdc nang gan, than, chup tim phdi CLJa ea 10 benh nhan deu khdng thay ddi sau 12 t u i n (T3) so vdi thdi diem (TO).
IV. BAN LUAN
Thuoc Tocilizumab (actemra) la mdt trong cac thudc khang the dan ddng nhan hoa tai to hap khang thu the inteuleukm 6 (IL-6) d i u tien da d y a c chLFng minh qua eac thy nghiem lam sang la thuoc d i i u tn hieu qua va an toan benh viem khdp dang t h i p dae bigt la eac benh nhan khdng ddp yng vdi cac phyang phap d i i u trj nhy thuoc giam dau chong vigm, thudc thay doi ca e h i smh benh DMADs, thude corticosteroid, va thudc sinh hoc LFC c h i y l u td hoai t y u TNF anpha [1, 2, 4, 5, 7] Trong n g h i e n cu'u nay ca 10 benh
• TAP CHI NGHIEN CU^J Y HOC nhan deu cd thdi gian dai dieu tri (tLF 1 nam
d i n 4,3 nam) b i n g cac loai thuoc ca ban tren (tuy nhign c h y a cd bgnh nhSn nao d y a e d i i u trj thudc smh hoe i>e c h i TNF anpha t r y d c dd) nhyng van khdng kiem soat d y a c qud trinh t l i n trien cua bdnh, han nCra cd 6/10 benh nhan ed tinh trang phu thude eorticoid vdi l i i u dung nhdm thudc eorticoid (medrol) hang ngay t y 4 - 32mg/ngay- Tuy nhien ehi sau 8 t u i n dieu tri b i n g actemra ea 6 benh nhSn nay da cd cai thign rd rang v i lam sang, xet nghigm, tinh trang bgnh d y a c k i i m soat, va da giam d y a e l i i u eorticoid dCing hang ngay. Sau 12 t u i n d i i u tri (sau 4 l l n truyin) cd 4/6 bgnh nhan da c l t d y a c thude eorticoid. Dae biet tinh trang kiem soat bdnh v i n d y a e duy tri sau 12 t u i n d i i u tn the hign d eac ehi sd lam sang; thang diem dau VAS giam tu' 8,7 diem tryde thdi diem d i i u tri (TO) xuong 1,9 d i i m sau 12 t u i n d i i u tn (T3), va s y khae bidt nay ed y nghTa thong kd vdi p < 0,01 (hinh l a ) Thdl gian cdng khdp buoi sang eCia benh nhan nghien OLFU t r y d e khi d i i u tn la 70,5 phut (NO), chi sd nay cung da giam rat nhiiu sau cae thdi diem nghign CLFU 65,3 phut (T1), 55,7 phut (T2) va d thai diem (T3) chi edn 33,8 phut (hinh l b ) , nhy vay thdi gian cyng khdp buoi sang da giam xudng d y d i 45 phut tdc la benh nhan da dat d y a c m y c dd on dinh benh.
K i t qua nay cung t y a n g t y nhy nghien CLFU cua cac tae gia khac [2, 5, 6, 7] S y dap yng tot vdi dieu tn thuoc Tocilizumab (aetemra) d 10 bdnh nhan viem khdp dang t h i p cung d y a c k h i n g dinh d s y cai thien cua cac ehi sd danh gia m y e dd hoat ddng benh. s6 cac khdp dau, sd cac khdp syng (hinh 2a) va chi so hoat ddng bdnh DAS 28-CRP cac bgnh nhan t r y d c thdi d i i m nghien c d u (TO) d i u d mLFc dd hoat ddng manh la 5,45 diem, tuy nhign sau 8 t u i n dieu tri Tocilizumab (aetemra), ehi sd DAS 28-CRP da giam xudng
m y c do hoat ddng trung binh 2,56 d i i m va sau 12 t u i n xudng d m y e dp dn dmh benh la 2,1 d i i m (hinh 2b) vdi p < 0 , 0 1
T y a n g t y cac ch! sd can ldm sang (bang 1}
d i u cho t h l y cd s y giam cua cae chi sd viem (toe do mau Ilng, ndng dd CRP) (p < 0,01) chLFng td tae dung y c c h l qua trinh vigm cua thuoc Tocilizumab (actemra) khi dc c h i y i u td IL-6 la mdt trong cae thanh p h l n trong pha viem khdi ddng va duy tri qua trinh viem man tinh tai mang hoat d[eh khdp cua benh nhan VKDT [4, 7] Dae biet la y i u t i dang t h i p RF cua benh nhan eung giam cd y nghTa thdng kg vdl p < 0,01 d thdi diem tryde d i i u tn (TO) la 158,2 IU/1 so vdi thdi diem sau 12 t u i n d i i u tn (T3) la 55,2 lU/l Tuy nhien ndng do hemoglo- bin trong mau ngoai vi cua benh nhan tuy ed tang Ign nhyng s y eai thien nay khdng ed s y khac bigt c6 y nghTa t h i n g ke vdi p > 0,01 K i t qua nghien eCfu nay khae vdi eae nghien CLFU [4, J, 6, 8] do thdi gian nghien OLFU cua chung tdi n g i n han n h i i u so vdi cac tae gia khdc Theo Nishimoto N [7] nghign cdu trgn 242 bgnh nhan vigm khdp dang t h i p , vdi 90%
bgnh nhan cd y i u td RF dyang tinh, chi sd DAS28 giam d i n 78% ngay sau 8 t u i n truyin b i n g tocilizumab (Actemra) 8mg/kg/4 t u i n va 40% sau 24 t u i n d i i u tn. khdng cd tac dung phLi cua thudc trong qua trinh dung thudc va theo ddi 6 thang d nhdm benh nhan nghign eiiu
Nhan xet v i tinh an toan cua thudc tocilizu- mab (Actemra) trong d i i u tri 10 benh nhan viem khdp dang t h i p , chung tdi khdng t h l y cd cac phan yng khdng mong muon trong, sau khl truyin thuoc eung nhy trong thdi gian theo ddl cac benh nhan sau 12 t u i n d i i u tn nhy cac k i t qua nghien CLFU da cdng bd nhy n h i i m k h u I n , n h i l m vius, phan LFng qua m i n [5, 7, 8] Tuy nhien d i cd k i t luan v i hieu qua cung nhy tinh an toan cua thudc tocilizumab (Aetemra) trong d i i u tn benh viem khdp dang
TCNCYH 80 (3)-2012
TAP CHI NGHIEN CU'U Y HOC • t h i p e i n phai cd so lyang SLF dung thudc cao han va cd thdi gian theo ddi d i i u tn dai han trong cac nghien CLFU t i i p theo-
V. K^T LUAN
Qua theo ddi d i i u tri 10 bgnh nhan vigm khdp dang t h i p cd y i u td RF d y a n g tinh vdi 12 t u i n d i i u tn b i n g tocilizumab (Actemra), bydc d i u cho t h l y tocilizumab (Actemra) cd hieu qua ro rdt trong cai thign tinh trang benh v i eac chi so lam sang va xet nghiem, cai thign chyc nang van dong khdp T h u i c Tocili- zumab (actemra) khdng gay tdc dung phu sau 12 tuan d i i u tn d 10 benh nhan viem khdp dang t h i p trong nghien CLFU nay
TAI LIEU THAM KHAO
1. Aarat MP, Larry W M (2010). Interieukin- 6 inhibitor for treatment of rheumatoid arthritis:
A revew of Tocilizumab therapy Drug Design Development and Thepapy 4 263-278
2. Emery P, Keyston E, Tony HP (2008).
IL-6 receptor inhibitor with Tocilizumab im- proves treatment in patients with rheumatoid arthritis recfactory to anti-tumor necrosis factor biologicis- results from i 24-weeks multi- benters randomised placebo-controlled trial Ann Rheum Dis 67, 1516 - 1523
3. Furst DE (2008). Update concensus statement on biological of rheumatic diseases
Ann Rheum Dis. 67 (3): 2 - 25
4. Fleishmann R, Burgos-Vargas R, A m b s E (2009). Tocilizumab mhiitor radio- graphic progresstion and improves physical function in rheumatoid arthritis patients at 2 years with increasing clinical efficalcy over time Proceedings of the American College of Rheumatology Annual Science Meerting 10"
1 7 - 2 1
^. Jones G, Sebba , Gu J (2010). Com- pansion of Tocilizumab monotherapy vernus methotrexat monotherapy in patients with moderate to severe rheumatoid arthritis. The AlVtBITION study Ann Rheum Dis, 69: 88 - 96
6. Margolier GR, Strand V (1997). Novel therapeutic agents for treatment of autoimmune diseases. Arthritis Rheum, 6 (6): 141-153-
/ . N i s h i m o t o N, Myasaka N, Yamamoto K (2009). Long-term safery and efficacy of Tocilizumab, and anti lL-6 receptor mono- clonal antibody in monotherapy in patients with rheumatoid arthritis (the STREAM study). Evi- dence of safety and efficacy in a 5-years exten- sion study Ann Rheum Dis 68 1580-1584,
8. Smolen J S , Beaulieu A, Rubber R (2008). Effects of interleukin 6 receptor inhibi- tion with Tocilizumab in patients with rheuma- toid arthritis (OPTION study). A double-blind placebo-eontrolled, randomised trial Lancet 371:987-997.
Summary
EFFICACY OF TOCILIZUMAB (ARTEMRA) IN RHEUMATOID ARTHRITIS TREATMENT
This study was carried out to determine the Tocilizumab (Artemra) efficacy and safely m rheuma- toid arthntis after 12 weeks treated The result showed that there was improvement of both clinical and disease activity such as VAS (from 7,7 to 1,9), DAS28-CRP (from 5 45 to 2 1) others inflamma- tion indeek (ESR, CRP) were significantly reduced with (p < 0-01)- No side effects of drug was rec- ognized In conclusion, Tocilizumab (Artemra) has efficacy in rtieumafo/darf^nf/s treatment.
Key w o r d s : rheumatoid arthritis, Tocilizumab (Artemra)
