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
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Figure 1. Study flow diagram. Reasons for withdrawal during the extension phase are included in the flow diagram.
508 patients enrolled and randomized
126 assigned to sequential monotherapy
(group 1)
6 withdrawals
120 patients completed 2-year follow-up
112 completed 2-year follow-up
125 completed 2-year follow-up
124 completed 2-year follow-up 121 assigned to
step-up combination therapy
(group 2)
133 assigned to initial combination therapy with prednisone
(group 3)
128 assigned to initial combination therapy
with infliximab (group 4)
9 withdrawals 8 withdrawals 4 withdrawals
5 withdrawals:
pat refusal (n=3) deceased (n=1) SAE (n=1)
115 patients completed 4-year follow-up
101 patients completed 4-year follow-up
119 patients completed 4-year follow-up
119 patients completed 4-year follow-up 11 withdrawals:
pat refusal (n=9) deceased (n=2)
5 withdrawals pat refusal (n=2)
deceased (n=1) SAE (n=1) other (n=1) 6 withdrawals:
pat moved from area (n=4) par refusal (n=1)
other (n=1)
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* Table 1. Primary outcomes during 4 years follow-up.
Sequential monotherapy
(Group1)
Step-up combi- nation therapy
(Group 2)
Initial combina- tion with pred- nisone (Group 3)
Initial combina- tion with inflixi- mab (Group 4)
P value
Mean (SD) improvement in health assessment questionnaire compared with baseline
3 years 0.8 (0.7) 0.7 (0.7) 0.8 (0.8) 0.9 (0.7) 0.66
4 years 0.8 (0.6) 0.7 (0.8) 0.8 (0.8) 0.8 (0.8) 0.64
Progression of Sharp-van der Heijde Score from baseline to 4 years follow-up Total score
Mean (SD) 11.7 (17.3) 9.7 (12.8) 6.7 (9.6) 5.4 (9.2)
Median (IQR) 5.0 (1.0-15.8) 5.5 (1.0-13.8) 3.0 (1.0-7.5) 2.5 (0.5-6.5) 0.005† Erosion score
Mean (SD) 6.0 (8.8) 5.7 (6.8) 3.0 (4.1) 3.0 (5.2)
Median (IQR) 3.0 (0.5-8.5) 3.5 (0.5-10.0) 2.0 (0.5-3.5) 1.5 (0.5-4.0) 0.001‡ Narrowing score
Mean (SD) 5.7 (10.0) 4.0 (7.0) 3.7 (6.7) 2.4 (4.6)
Median (IQR) 1.8 (0.0-7.0) 1.0 (0.0-4.5) 1.0 (0.0-3.9) 1.0 (0.0-2.5) 0.17 SD, Standard deviation; IQR, interquartile range; † group 1 versus group 2, P=0.77; group 1 versus group 3, P=0.06; group 1 versus group 4, P=0.002; group 2 versus group 3, P=0.10; group 2 versus group 4, P=0.005;
group 3 versus group 4, P=0.18. ‡ P <0.05 for all comparisons of groups 1 and 2 versus groups 3 and 4.
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Figure 2. Cumulative probability distribu- tion of total Sharp-van der Heijde Score over 4 years of treatment with sequential monotherapy, step-up combination ther- apy, initial combination therapy including prednisone or initial combination therapy including infliximab. The smallest detect- able change (SDC) was 4.6 Sharp units and is represented by the horizontal line.
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Change from baseline (sharp units)
initial combination with infliximab initial combination with prednisone step-up combination therapy sequential monotherapy
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Table 2. Baseline differences between patients who did or did not achieve drug-free remission after 4 years.
Drug-free remission N=67
No drug-free remission N=441
p-value
Age, years 56 (15) 54 (14) 0.45
Males, no. (%) 35 (52) 130 (29) <0.001*
Time from diagnosis to inclusion, weeks (median, IQR)
2 (1-4) 2 (1-5) 0.63
Symptom duration, weeks (median, IQR) 18 (11-33) 24 (14-56) 0.007*
IgM rheumatoid factor negative, no. (%) 32 (48) 147 (33) 0.02
Anti-CCP negative, no. (%) 38 (57) 144 (36) 0.001*
DAS 4.1 (0.8) 4.5 (0.9) 0.004
HAQ, 0-3 scale 1.2 (0.6) 1.4 (0.7) 0.002
VAS pain (mm) 45 (22) 55 (22) 0.001
VAS disease activity (mm) 55 (19) 61 (23) 0.04
VAS morning stiffness (mm) 54 (24) 60 (24) 0.04
Erosive, no (%) 44 (69) 313 (72) 0.60
Total SHS, 0-448 scale (median, IQR) 3.3 (1.0-6.9) 4.0 (1.5-9.0) 0.18
* Independently associated with drug-free remission after 4 years. Values are the mean (SD) unless indi- cated otherwise. IQR, interquartile range; DAS, disease activity score (44 joints); HAQ, health assessment questionnaire; VAS, visual analog scale; SHS, modified Sharp/van der Heijde Score.
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I:MB>GML K>@:K=E>LL GB<:GMER Figure 3. Percentage of patients on different treatment steps, including the occurrence of drug-free remis- sion (no DMARD) in 4 different treatment strategies during 4 years of follow-up. No DMARD, drug-free remission; MTX, methotrexate; SSA, sulfasalazine; LEF, leflunomide; IFX, infliximab; CSA, cyclosporine A;
pred, prednisone; AZA, azathioprine; step-up combi, patients treated with MTX + SSA( + hydroxychloro- quine, + prednisone); other, in groups 1-3: patients in treatment steps beyond MTX + IFX, and in group 4:
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Table 3. Adverse events and serious adverse events during 4 years follow-up.
Group 1 Group 2 Group 3 Group 4 P-value AE
Any AE during 4 years 103 (82) 100 (83) 106 (80) 107 (84) 0.87
Any AE in year 3-4 76 (60) 74 (61) 76 (57) 82 (64) 0.72
Infectious year 3-4 31 (25) 35 (29) 24 (18) 32 (25) 0.23
Gastro intestinal year 3-4 18 (14) 13 (11) 17 (13) 21 (16) 0.61 Dermal / mucosal year 3-4 16 (13) 16 (13) 18 (14) 12 (9) 0.72
Neurological year 3-4 9 (7) 11 (9) 3 (2) 16 (13) 0.02‡
Cardiovascular year 3-4 5 (4) 7 (6) 13 (10) 11 (9) 0.25
Infusion reactions year 3-4 (no.) 1 0 1 2 0.58
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Total SAEs during 4 years (no.) 57 45 60 47 0.31
Serious infections during 4 years (no.) 12 2 5 6 0.03†
Malignancies during 4 years (except non-melanoma skin cancers; no.)
3 4 5 1 0.44
Non-melanoma skin cancers during 4 years (no.)
2 0 1 3 0.35
Deaths during 4 years (no.) 1 3 1 3 0.53
Values indicate the number (percentage) of patients unless indicated otherwise. AE, adverse event; SAE, serious adverse event. ‡ P<0.05 for group 3 versus group 4; † P<0.05 for group 1 versus group 2. Causes of death per group were the following, in group 1: pneumonia, antibiotic treatment refused (year 3); group 2:
cerebrovascular accident (year 2); bronchial carcinoma and myocardial infarction (both year 4); group 3:
ovarian carcinoma (year 2); group 4: disseminated tuberculosis* [24] and myocardial infarction (both year 2); septic arthritis* (year 3). *deaths judged to be possibly related to treatment with infliximab.
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