Strategies for optimal suppression of rheumatoid arthritis
Kooij, S.M. van der
Citation
Kooij, S. M. van der. (2009, January 22). Strategies for optimal suppression of rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/13425
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the
University of Leiden
Downloaded from: https://hdl.handle.net/1887/13425
Note: To cite this publication please use the final published version (if
applicable).
-',NBM>KF:G
$"&'
FF
;LMK:<M
);C><MBO>L.H
=KN@
HGL>M
'>MAH=L#G
PBMA
<B>GM
?:BENK>L
G:EER AR=KHQR<AEHKHJNBG>
'.2≤ FHGHMA>K:IR :LL>LL>=
,>LNEML?M>K
<B>GM L>JN>GMER
.--
HG<ENLBHG?M>K
', L≤
&BFBM>=
', L
?:BENK>
KA>NF:MHB=
MH
,A>NF:MHB=
:G=
;>>G : BG MBOBMR 5 7
&:K@>
MBHG
=>GBMBHGL
-BG<>
:<AB>OBG@
IHKM:GM K>@NE:K MB>GML FHGBMHKBG@
#G
<EBGB<:E :=CNLMF>GML≤ IHLM I:MB>GML HK
*:MB>GML
*:MB>GM
.A>
K:=BHEH@B<:E
<>GM MN:EER P>K>
-MN=R
.A>
<>LL≤ PAB<A
-
,#
:L MBHG
<NE:MBHGL BGLM:GMER H?
=HL>
F>GM
#?≤ LBG@E>
I>K>=
I>K>=
>??><MBO>
IKH<>>=>=
Group 1 Methotrexate 7.5 mg/week,
increased to 15 mg/week after 4 weeks
Methotrexate 25 mg/week
Sulfasalazine 2000-3000 mg/day
Leflunomide 20 mg/day
Methotrexate 25 mg/week Infliximab 3 mg/kg/8 weeks with possible dose increase to 6 mg/kg, 7.5 mg/kg and 10 mg/kg
Sodium aurothiomalate 50 mg/week Depomedrol 120 mg at week 1, 4 and 8
Methotrexate 25 mg/week Cyclosporine 2.5 mg/kg/day in 2 doses
Prednisone 7.5 mg/day
Azathioprine 2-3 mg/kg/day Prednisone 7.5 mg/day
Group 2 Methotrexate 7.5 mg/week,
increased to 15 mg/week after 4 weeks
Methotrexate 25 mg/week
Methotrexate 25 mg/week Sulfasalazine 2000-3000 mg/day
Methotrexate 25 mg/week Sulfasalazine 2000-3000 mg/day Hydroxychloroquine 400 mg/day
Methotrexate 25 mg/week Infliximab 3 mg/kg/8 weeks with possible dose increase to 6 mg/kg, 7.5 mg/kg and 10 mg/kg
Methotrexate 25 mg/week Cyclosporine 2.5 mg/kg/day in 2 doses
Prednisone 7.5 mg/day
Leflunomide 20 mg/day
Sodium aurothiomalate 50 mg/week Depomedrol 120 mg at week 1, 4 and 8
Azathioprine 2-3 mg/kg/day Prednisone 7.5 mg/day Methotrexate 25 mg/week Sulfasalazine 2000-3000 mg/day Hydroxychloroquine 400 mg/day
Prednisone 7.5 mg/day
Figure 1. Protocol for escalation of disease modifying antirheumatic therapy in patients with persisting dis- ease activity (DAS 2.4). The DAS was calculated every 3 months.
#G
>K:M>=
MH
=KN@L MHKR
?<:<R
*:MB>GML≤ F:BG>=
:<AB>O>≤ IKHMH<HE
@KHNIL K>LNEMBG@
L JN>LMBHGBG@
K>LNEM PA>MA>K MK>:MBG@
MH<HE :<MN:E M>KFBG>=
HK≤
,:=BHEH@B<:E R>:KL :LL>LLHKL K:G=HF P:L NGBML
-M:MBLMB<:E
B??>K>G<>Lχ ':GG1ABMG>R
-
M>LM>=
MA>
?HKF>=
P>K>≤
?HK M>KBLMB<L
EE
*O:EN>L
,>LNEML
O:EN:MBHG
:L>EBG>
HG>≤ :G=≤
?M>K≤ HG F@ P>>D FHGMAL
≤
'.2
?M>K
HG>
Table 1. Demographic and disease characteristics at baseline of patients randomised to sequential mono- therapy and step-up combination therapy.
Sequential monotherapy (n = 126)
Step-up combination therapy (n = 118)
Age (years) 54 (13) 54 (13)
Female sex (%) 68 72
Time diagnosis inclusion (weeks), median (IQR) 2 (1-5) 2 (1-4)
Symptom duration (weeks), median (IQR) 23 (14-54) 26 (13-54)
IgM rheumatoid factor positive (%) 67 64
Body weight (kg) 76 (14) 75 (14)
NSAID use (%) 89 84
ESR (mm in 1st hour) 48 (31) 38 (25)
Tender joints 15 (7.7) 14 (6.6)
Swollen joints 15 (6.6) 15 (6.9)
DAS 4.5 (0.9) 4.4 (0.8)
HAQ (0-3) 1.4 (0.7) 1.4 (0.6)
Total Sharp Score (0-448 scale), median (IQR) Mean (SD)
4 (2-10) 7 (10)
5 (2-9) 6 (7) Erosion score (0-280 scale), median (IQR)
Mean (SD)
2 (0.5-5) 4 (6)
2 (0.5-5) 4 (4) Narrowing score (0-168 scale), median (IQR)
Mean (SD)
1 (0-4) 3 (5)
2 (0-5) 3 (3)
Erosions on hand/foot radiograph (%) 73 72
IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; ESR, erythrocyte sedimentation rate; DAS, disease activity score (44 joint count); HAQ, health assessment questionnaire. Values are given in mean (SD) if not indicated otherwise. When not normally distributed, medians and IQRs of variables are reported.
≤ '.2
>K:M>
'.2 LN<<>LL>L
>G<>L
:L>EBG>
L>Q MBO:KB:M>
?>F:E>
,:=BH@K:IAB<
,:=BH@K:IAL I:MB>GML GNF;>KL F>=B:G
-
Table 2. Demographic and disease characteristics at baseline of ‘MTX successes’ and ‘MTX failures’.
MTX successes*
(n = 79)
MTX failures*
(n = 162)
P-value
Age at diagnosis (years) 56 (14) 54 (13) 0.455
Female sex (%) 56 77 0.001†
Time diagnosis inclusion (weeks), median (IQR) 3 (1-6) 2 (1-4) 0.022 Symptom duration (weeks), median (IQR) 23 (12-53) 26 (15-55) 0.367
IgM rheumatoid factor positive (%) 62 67 0.420
ESR (mm in 1st hour) 39 (27) 45 (29) 0.142
Tender joints 12 (6.8) 16 (6.8) 0.001
Swollen joints 15 (7.1) 15 (6.5) 0.709
DAS 4.2 (0.9) 4.7 (0.8) 0.001†
HAQ (0-3) 1.2 (0.7) 1.5 (0.6) 0.001
Total Sharp Score (0-448 scale), median (IQR) Mean (SD)
3.5 (1-8.5) 7 (9)
4.5 (1.5-9) 7 (8)
0.350
Erosions on hand/foot radiograph (%) 72 74 0.713
* ‘MTX successes’ are patients with a DAS ≤2.4 after 2 years while still on MTX monotherapy. ‘MTX failures’
are patients who discontinued MTX because of a DAS 2.4 or adverse events. IQR, interquartile range;
ESR, erythrocyte sedimentation rate; DAS, disease activity score (44 joint count); HAQ, health assessment questionnaire; MTX, methotrexate. Values are given in mean (SD) if not indicated otherwise. When not nor- mally distributed, medians and IQRs of variables are reported. Significance between variables was tested by Student t test for normally distributed continuous variables; Mann-Whitney U test for non-normally distributed variables; χ2 test for dichotomous variables. For total Sharp score, both median (IQR) and mean (SD) are given; significance was tested by the Mann-Whitney U test. † Independent predictor for ‘MTX failure’ after logistic regression analysis.
?M>K NK>L
F>=B:G :G=
BG PAH≤
G
O:EN:MBHG
NKBG@
<>>=>=≤ --
: LNLM:BG>=≤
;><:NL>
)O>K:EE BG
<K>:L>=
N>=
Figure 2. Drug survival on different DMARDs for patients in groups 1 and 2 (Kaplan-Meier survival curves). Discontinuation of DMARDs because of insufficient clinical success (that is, DAS 2.4), toxicity or other reasons. The numbers depicted in the survival curves in- dicate the - number of patients still treated according to the respective treatment step at that time. (A) MTX monotherapy, group 1 versus group 2; (B) SSA (group 1) versus MTX + SSA (group 2); (C) LEF (group 1) versus MTX + SSA + HCQ (group 2).
0 3 6 9 12 15 18 21 24 0
20 40 60 80
100 group 1 (n=126) group 2 (n=118)
A
p=0.527 109
58
41
37 117
68 47
42
time on MTX (months)
Percent survival
0 20 40 60 80 100
Percent survival
0 3 6 9 12 15 18 21 group 1 (n=69) group 2 (n=69)
B
p=0.690 29
25 21
17 16 15
18 15
time on SSA (months)
0 3 6 9 12 15 18 21 0
20 40 60 80
100 group 1 (n=54) group 2 (n=44)
C
p=0.028 22 22
19
11 9 17
time on 3rd DMARD (months)
Percent survival
#G FHK>
LN<<>LL>L
MHKL HK H?
O:EN:MBHG
NKBG@
MH≤ E>NGHFB=>
H?
:≤
>B@AM Table 3. Total Sharp/van der Heijde score progression after 2 years in ‘MTX successes’ and ‘MTX failures’.
MTX successes (n = 73)
MTX failures (n = 140)
P-value
TSS, median (IQR) 1 (0-5) 3 (0.5-10) 0.007†
TSS, mean (SD) 3 (5) 9 (17)
Patients with TSS SDC (%) 29 42 0.056
TSS, total Sharp/van der Heijde score; IQR, interquartile range; SDC, smallest detectable change (4.6 units); MTX, methotrexate; † by Mann-Whitney U test.
Table 4. Demographic and disease characteristics at baseline* of ‘SSA successes’ and ‘SSA failures’
SSA successes (N=30)
SSA failures (N=108)
P-value
Age at diagnosis (years) 56 (13) 53 (13) 0.223
Female sex (%) 60 81 0.014†
Time diagnosis inclusion (weeks), median (IQR) 2 (1-4) 2 (1-4) 0.611 Symptom duration (weeks), median (IQR) 22 (15-34) 29 (14-57) 0.278
IgM rheumatoid factor positive (%) 67 71 0.620
ESR (mm in 1st hour) 24 (14) 31 (23) 0.108
Tender joints 8 (4) 12 (6) 0.009
Swollen joints 7 (6) 9 (7) 0.075
DAS 3.2 (0.7) 3.7 (0.8) 0.003†
HAQ (0-3) 0.9 (0.5) 1.2 (0.7) 0.018
* Values of ESR, tender joints, swollen joints, DAS and HAQ were obtained at the start of SSA treatment.
IQR, interquartile range; ESR, erythrocyte sedimentation rate; DAS, disease activity score (44 joint count);
HAQ, health assessment questionnaire. Values are given in mean (SD) if not indicated otherwise. When not normally distributed, medians and IQRs of variables are reported. Significance between variables was tested by Student t test for normally distributed continuous variables; Mann-Whitney U test for non-nor- mally distributed variables; χ2 test for dichotomous variables. †Independent predictor for ‘SSA failure’ after logistic regression analysis.
L
#G≤ HG P:L :≤
:<AB>O>=≤ JN>GM HK
O:EN:MBHG
NKBG@≥
MH
≤
;>@:G
≤
MA>
HG>
BL<NLLBHG
.A>≤ HMK>Q:M>
<EBGB<:E LM>IL K>LNEM>=≤
100 75
50 25
0
Cumulative probability 100
80
60
40
20
0
Radiographic progression (sharp units)
‘MTX successes’
‘MTX failures’
Figure 3. Cumulative probability plot of individual 2 year radiographic progression scores in 213 rheumatoid arthritis patients who participated in the BeSt trial (73 ‘MTX successes’ (triangles) and 140 ‘MTX failures’
(circles)). Cumulative probability was calcu- lated per group.
=>KBO>=
M:BG>=≤
.ABL≤ '.2 GB<:GMER≤ MB:E MA>K:IR EB>K
?HK BFIKHO>=
H?
K:=BH@K:IAB<
MK>:MF>GM K>LIHGL>
HNL
)G>
=BL<HGMBGN:MBHG
>O>G
"HP>O>K
>-M :IR
=:M:
PBMA PBMA :
=:M:
IK><BL>ER
?M>K GH
=N<>=
LMN=R --
H;L>KO:MBHGL
<HF;BG:MBHG
≤
;R LPBM<A>=
PAH --
*:MB>GML MK>:M>=
H?≤ .A>L>
<EBGB<:E
HMK>Q:M>
:GM:@HGBLML 57 MABL IHINE:MBHG JN:=KNIE>
HG
#G ,≤
<>LL
<EBGB<:E
=>O>EHI MA:M MBO>
=>E:R>=
<EBGB<:E
BG LMK:M>@R
F>GM IK:<MB<>
F>GM ,A>NF:MBLF
HFI:KBLHG ,A>NF:MHEH@R G:MBHG:E ,@=ME
-A:KI
IKH@K>LLBHG I:MB>GML
,@=ME
F>GM
<HFI:KBLHG F>GM
:?M>K BG ,@=ME
G>LL
=KN@L
:M>
,
5:;LMK:<M7
:M>=
BG
<:<R :KMAKBMBL IABLFL LAK
SBG>
BFIEB<:MBHGL BG
:IR MA:G MBL
?KHF
FF
MA>K:IR
<HGMKHEE>=
IA:L:E:SBG>
<HFIHG>GML
LNEIA:L:E:SBG>
IHG>GML MKHEE>=
MHB=
F>MAHMK>Q:M>
MAK>>
=HN;E>;EBG=
;EBG=
<HF;BG>=
PBMA
F:;
:KMAKBMBL
<HF>
R>:KL
E>NGHFB=>
:<MBO>
FNEMB<>GMK>
&9F;=L
F:MHB=
:G=
#GO>LMB@:MHKL
BG
',
:G<AHK MBL
:GMBKA>NF:MB<
HGL>M HMK>Q:M>
<HAHKM HMK>Q:M>
,@=ME
=HL>
BLHG MA>
<:E
HG M>F:MB<
,@=ME9LGDG?Q
F>GM I:MB>GML ,@=ME9LGDG?Q
F>MAHMK>Q:M>
NGNLN:E
FF
/- MHB=
:KMAKBMBL
=>I>G=>GM :GMBKA>NF:MB<
LAGF9D
LABI I:MB>GML LBL
M>F:MB<
BMR
<HGMKHEE>=
>M MK>:MF>GM :KMAKBMBL
JL@JALAK
LMK:M>@R .# ),
MKB:E
MK>:MF>GM MBL
,>?>K>G<>L
KMAKBMBL '=<
@K:IAB<
PBMA FHGH<EHG:E :KMAKBMBL
,@=ME
MB<
:M>
KA>NF:MHB=
E>=
