TNF blockade in daily practice
Bijl, A.E. van der
Citation
Bijl, A. E. van der. (2010, March 9). TNF blockade in daily practice. Retrieved from https://hdl.handle.net/1887/15056
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Chapter 6
Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis
AE van der Bijl, YPM Goekoop-Ruiterman, JK de Vries-Bouwstra, S ten Wolde, KH Han, MV van Krugten, CF Allaart, FC Breedveld, BAC Dijkmans
Arthritis Rheum 2007; 56(7): 2129-34.
abstract objective
To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA).
methods
DMARD-naive patients with active, early RA who were included as group 4 of the BeSt study, were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. For patients with persistent low disease activity (DAS ≤2.4) for at least 6 months, inflixi- mab was tapered and finally discontinued, followed by tapering MTX to 10 mg/week.
In patients with DAS >2.4 the infliximab dosage was increased (maximum 10 mg/kg) and subsequently switched to another DMARD. Corticosteroids were, besides intra- articular administration, not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy.
results
Of the 120 patients, 67 (56%) had persistent low disease activity and discontinued infliximab after (median) 9.9 months with a median MTX dose of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resu- med infliximab after (median) 3.7 months. Thirteen patients did not achieve persistent low disease activity and received various infliximab dosages. Thirty patients were classified as Failures. In the 67 Responders the progression of joint damage was lower than in the 30 Failures.
conclusion
Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS ≤2.4. Low disease activity was maintained in these patients while MTX was tapered to 10 mg/week.
introduction
In order to prevent progression of joint damage and functional disability, early intro- duction of effective disease-modifying anti-rheumatic drugs (DMARDs) is conside- red to be essential in the treatment of patients with rheumatoid arthritis (RA)(1-5).
Biologic agents, particularly tumor necrosis factor (TNF) inhibitors, were initially developed to treat patients with active disease despite conventional DMARDs. More recently, TNF-inhibitors were shown to be more effective than methotrexate (MTX) as treatment for patients with newly diagnosed RA(6-8). To date, the high costs of these drugs and the uncertainties about the risk of adverse effects from prolonged usage are among the reasons why treatment with a TNF-inhibitor is not the initial therapy for many patients recently diagnosed with RA(9).
An evaluation of ten patients indicated that early treatment of RA with infliximab may induce a permanent response that persisted even after discontinuation of the drug(7).
In the BeSt study, comparing different strategies in patients with early, active RA to measure clinical and radiological outcomes, the combination of infliximab and MTX was one of the initial treatments(10). The protocol required a decrease of the inflixi- mab dosage and finally discontinuation, once a DAS score not exceeding 2.4 was achieved for at least 6 months. We performed a separate analysis of the disease and treatment course of 128 patients randomized to the initial infliximab plus MTX stra- tegy, in order to examine the effectiveness of infliximab as induction therapy.
patients and methods patients
Patient data included in this analysis were derived from the BeSt study conducted by rheumatologists participating in the Foundation for Applied Rheumatology Re- search. Patients with early RA, as defined by the American College of Rheumatology (ACR) 1987 criteria(11), were recruited between March 2000 and August 2002 at 20 centers in the Netherlands. Patients had a maximum disease duration of 2 years, were at least 18 years of age and had active disease defined as ≥6/66 swollen joints,
≥6/68 tender joints and either an erythrocyte sedimentation rate (ESR) ≥28 mm/hr or a Visual Analogue Scale (VAS) global health assessment ≥20 mm (on a scale of 0 to 100 mm, 0=best, 100=worst). Exclusion criteria included previous treatment with DMARDs other than antimalarials, concomitant treatment with an experimental drug, a malignancy within the previous 5 years, bone marrow hypoplasia, a serum aspar- tate aminotransferase/alanine aminotransferase >3 times the upper limit of normal, a serum creatinine >150 µmol/L or an estimated creatinine clearance <75 mL/min, dia- betes mellitus, alcohol or drug abuse, concurrent pregnancy, plans to conceive during the study period or inadequate contraception. Local ethics committees approved the study protocol, and all participants provided written informed consent.
study design
The BeSt study is a randomized trial to compare the clinical and radiographic out- comes of 4 different treatment strategies(10): sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered
high-dose prednisone (group 3), and initial combination therapy with the TNF anta- gonist infliximab (group 4). The common goal in all strategies was to reduce disease activity rapidly and persistently by tight monitoring and immediate adjustment of therapy in the case of an insufficient response. A total sample size of 468 patients (117 per group) was needed to obtain 80% power to detect a difference of at least 0.2 in the HAQ score, which was set as a clinically relevant difference, with a 5% signifi- cance level and adjusting for multiple comparisons between groups, assuming an SD of 0.45. This sample size also ensured >80% power to detect a difference of ≥20% in the change score of radiographic damage as measured by the SHS. For the current descriptive manuscript we selected the patients in group 4 who were initially treated with the combination infliximab plus methotrexate. Treatment adjustments were based on the Disease Activity Score (DAS) comprised of the Ritchie articular index, swollen joint count, ESR and general health assessed by a visual analogue scale(12) that was measured every 3 months and 1 to 2 weeks prior to each infliximab infusion by a research nurse who remained blinded for the allocated treatment strategy. Good clinical response to therapy was defined as a DAS score less than or equal to 2.4, indi- cating low disease activity (12). According to the protocol, in case of persistently low disease activity (DAS ≤2.4 for at least consecutive 6 months) treatment was tapered to a single DMARD at a maintenance dose.
Concomitant treatment with nonsteroidal antiinflammatory drugs and intra-articular injections with corticosteroids were permitted. Other parenteral corticosteroids were not allowed before and during the study period. The use of DMARDs or oral corticos- teroids was only permitted as dictated by the treatment protocol. All patients received 1 mg/day folic acid during treatment with MTX.
For the current analysis, only patients randomized to group 4 were included. These patients were initially treated with the combination of infliximab (3 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter) and MTX (25 mg/week). Methotrexate was started in the highest dose to ensure that later improvements in disease activity could be attributed to infliximab and not to later increases of methotrexate. If the DAS remained above 2.4 the infliximab dosage was increased to 6 mg/kg, 7.5 mg/kg and finally 10 mg/kg. If, after the increase in infliximab dose, the DAS remained above 2.4, the patients discontinued the combination of infliximab plus MTX and switched to SSA.
In patients with a DAS less than or equal to 2.4 for a period of at least 6 months, the infliximab dose was tapered at each consecutive infusion (10 mg/kg→7.5 mg/
kg→6 mg/kg →3 mg/kg) and finally discontinued. Patients received at least seven infliximab infusions at weeks 0, 2, 6, 14, 22, 30 and 38. If the DAS did not exceed 2.4 after infliximab discontinuation, the MTX was tapered to a minimum of 10 mg/week.
In case of a disease flare (DAS >2.4) the last effective dose of infliximab or MTX was given or the last discontinued drug, i.e. infliximab, was reintroduced. Once patients restarted treatment with infliximab no further attempts were made to discontinue the infliximab; patients who again achieved a DAS less than or equal to 2.4 remained on a maintenance dose of 3 mg/kg every 8 weeks.
study evaluations
All DAS measurements, HAQ scores and changes in therapy were recorded in the first 2 years of the still ongoing BeSt study. Radiographs of the hands and feet at baseline and 2 years were evaluated, using the Sharp/van der Heijde score (SHS). All radio- graphs were read by 2 trained assessors (G-R, V-B) who were blinded to the patient’s identity, treatment center, and date of radiograph and who scored the radiographs paired, in random order, and independently. The intraobserver coefficients were 0.93 and 0.94, and the interobserver coefficient was 0.93. The mean score of the 2 asses- sors was used for the analysis. Progression of joint damage was defined as an SHS equal to or exceeding the smallest detectable change (SDC) calculated as a change of the SHS ≥4.64(13).
statistical analysis
Measures with a Gaussian distribution, expressed as mean and standard deviation (SD), were analyzed using a one-way analysis of variance (ANOVA). In case of an overall significant difference between the groups, a post-hoc least squares difference (LSD)-test was performed. Outcome measurements with a non-Gaussian distribution, expressed as median and interquartile range (IQR), were analyzed by the Kruskal-Wal- lis test. Pair-wise comparisons between groups were performed using the Mann-Whit- ney U test. Categorical variables such as rheumatoid factor and gender were analyzed using the chi-square test.
results
patient characteristics and disposition
At baseline, 128 patients were randomized to initial treatment with infliximab plus MTX. These patients had a mean (SD) age of 54 (14) years, a mean (SD) DAS of 4.3 (0.9) and a median (IQR) symptom duration of 23 (13-46) weeks. Sixty-four percent (82/128) of the patients were rheumatoid factor positive and 73% (93/128) already had erosions with a median (IQR) SHS of 4.0 (1.5-8.5). Four patients did not receive the combination therapy because of a contraindication for infliximab. An additional four patients were excluded from the current analysis because they discontinued treatment for the following reasons: refusal of infliximab therapy (n=1), withdrawal of consent within 2 months (n=1), or revised diagnosis (n=2) (Figure 1). A total of 120 patients completed the 2-year study period and were included in the current analysis.
clinical course
• Responders
During the follow-up period, 77 out of 120 patients (64%) achieved a DAS less than or equal to 2.4 for at least 6 months and discontinued infliximab administration. Of those 120 patients, 52 (68%) were in clinical remission (DAS <1.6) at the time that infliximab therapy was discontinued. Sixty-seven of these 77 patients, i.e. 56% of the total number of patients included, were able to permanently discontinue the inflixi- mab during the 2-year follow up. These patients were classified as Responders. Of the 67 Responders, 28 (42%) initially required an increase in the infliximab dosage above
figure 1: Patient disposition through 2 years of follow-up
128 patients assigned to group 4:
combination IFX+MTX
8 patients were not included for analysis (contraindication IFX (n=4), revised diagnosis (n=2) or other reasons (n=2)) 120 patients started IFX 3mg/kg + MTX
46 patients discontinued IFX because of good response 7 restarted
65 patients progressed to IFX 6 mg/kg
23 patients tapered and discontinued IFX because of good response 2 restarted
39 patients progressed to IFX 7.5 mg/kg
3 patients remained on variable dosages because of DAS fluctuations
5 patients tapered and discontinued IFX because of good response 1 restarted
4 patients remained on variable dosages because of DAS fluctuations
30 patients progressed to IFX 10 mg/kg
3 patients tapered and discontinued IFX because of good response
5 patients remained on variable dosages because of DAS fluctuations
22 patients continued treatment with other DMARDs
8 patients stopped therapy because of side
effects
1 patient remained on IFX 3mg/kg
figure 1: Patient disposition through 2 years of follow-up
3 mg/kg before achieving a DAS less than or equal to 2.4. The maximum infliximab dosages required were 6 mg/kg in 21 patients, 7.5 mg/kg in 4 patients and 10 mg/kg in 3 patients. The median (IQR) duration of the infliximab therapy before discontinu- ation in the Responders was 9.9 months (8.7-14.9). At the time of infliximab discon- tinuation the mean (SD) DAS was 1.3 (0.6). Most Responders were able to taper the MTX dose as a result of a DAS less than or equal to 2.4. Following 2 years of treat- ment, the median MTX dose was 10 mg/week (mean 12.4) and the mean (SD) DAS was 1.4 (0.6).
• Patients requiring continued infliximab treatment
Of the 77 patients who discontinued infliximab therapy after achieving a DAS less than or equal to 2.4 for at least 6 months, ten (13%) had a disease flare (DAS >2.4) and reintroduced infliximab treatment after 3.7 months (median, IQR 3.2-6.5). Three of these patients required infliximab dosages above 3 mg/kg before achieving a DAS less than or equal to 2.4 for at least 6 months. At the time of infliximab discontinuation the mean (SD) DAS among these patients was 0.95 (0.6). After the 2 years of follow up studied eight patients regained a low-level disease activity (DAS ≤2.4) with infliximab dosages of 3 mg/kg (n=4), 6 mg/kg (n=2), 7.5 mg/kg (n=1) or 10 mg/kg (n=1); one patient had to restart infliximab at the 2-year time point and one patient increased the infliximab dose to 6 mg/kg because of a DAS >2.4 at the 2-year time point.
Thirteen (10%) of the 120 patients included in this analysis were not able to discon- tinue infliximab treatment, but remained on variable doses over a period of 2 years.
These patients either did not achieve a DAS less than or equal to 2.4 for at least 6 consecutive months or experienced a disease flare after tapering infliximab and re- quired an increase in the infliximab dose. Infliximab dosage adjustment was repeated as necessary. The maximum infliximab dosages were 3 mg/kg (one patient), 6 mg/kg (three patients), 7.5 mg/kg (four patients) and 10 mg/kg (five patients). All patients who were remained on infliximab treatment after two years were classified as Conti- nued Infliximab Treatment (10+13=23).
• Failures
Twenty-two patients (22/120, 18%) did not reach a DAS less than or equal to 2.4 des- pite increasing infliximab dosages to 10 mg/kg every 8 weeks. According to the study protocol, these patients were switched to the next treatment, SSA (2 g/day), following a median (IQR) period of treatment with infliximab and MTX of 12.4 months (9.7-15).
An additional eight patients (8/120, 7%) experienced adverse effects from infliximab and/or MTX treatment and were also switched to SSA. The patients that were inflixi- mab failures and those that discontinued because of adverse effects were both classi- fied as Failures (n=22+8=30).
comparisons across response groups
The 30 Failures had significantly higher baseline DAS and HAQ scores when compared with the 67 Responders (Table). The baseline HAQ score was also higher for Failures compared with the 23 patients requiring Continued Infliximab Treatment, however, the baseline DAS values were not significantly different between these two patient groups. Baseline SHS scores were similar across patient groups (p=0.89; Table).
At the end of the study period Responders had significantly lower DAS values, which
were reflected in the significantly lower HAQ scores. After 2 years of treatment the mean SHS values were not significantly different among the three groups, however, the median progression of the SHS score was significantly higher in the Failures than in the Responders (Table and Figure 2). In addition, the percentage of patients with progres- sion of joint damage (SHS≥SDC) was higher among the Failures (37%) than both the Responders (9.4%) and those with Continued Infliximab Treatment (20%; Table).
table: Clinical characteristics at baseline and after 2 years follow up.
DAS= disease activity score; HAQ: health assessment questionnaire; SDC= smallest detectable change; SHS= modified Sharp/van der Heijde score.
Failure vs. Responder p=0.01, others not significant;
† Failure vs. Responder p<0.01, Responder vs. Continued infliximab treatment p<0.01, failure vs.
Continued treatment p=0.15;
‡ Failure vs. Responder p<0.01, Failure vs. Continued infliximab treatment p<0.01, others not significant;
§ Failure vs. Responder p<0.01, Failure vs. Continued infliximab treatment p<0.01, others not significant; Failure vs. Responder p<0.01, others not significant;
Failure vs. Responder p<0.01, others not significant.
Responder (n=67)
Continued infliximab treatment
(n=23)
Failure (n=30)
Overall p-value
DAS; mean (SD) Baseline 4.1 (0.7)
4.3 (1)
4.6 (0.9)
0.04
2 year 1.4 (0.6)
2.2 (0.8)
2.7 (0.8)
<0.01†
HAQ; mean (SD) Baseline 1.3 (0.7)
1.2 (0.5)
1.7 (0.6)
<0.01‡
2 year 0.3 (0.4)
0.5 (0.5)
0.9 (0.6)
<0.01§
SHS; mean (SD) Baseline 6.9 (10.6)
5.4 (5.6)
7.8 (11.3)
0.89
2 year 8.3 (11.2)
7.9 (9.4)
12.7 (14.6)
0.29
SHS; median (IQR) Baseline 3.8 (1-7.1)
3 (1.5-7)
4 (0.9-10.6)
0.89
2 year 4.5 (1.5-11)
4.3 (0.8-13.1)
6 (2-24.5)
0.29
ΔSHS; mean (SD) 1.5
(3.4)
2.9 (4.8)
5 (6)
0.01¶
ΔSHS; median (IQR) 0.5
(0-2)
1.5 (0-4.4)
2.5 (0-7)
0.01¶
Patients with SHS≥SDC (%) after 2 year follow up
9.4 20 37 <0.01
table: Clinical characteristics at baseline and after 2 years follow up.
DAS= disease activity score; HAQ: health assessment questionnaire; SDC= smallest detectable change; SHS= modified Sharp/van der Heijde score.
* Failure vs. Responder p=0.01, others not significant;
† Failure vs. Responder p<0.01, Responder vs. Continued infliximab treatment p<0.01, failure vs.
Continued treatment p=0.15;
‡ Failure vs. Responder p<0.01, Failure vs. Continued infliximab treatment p<0.01, others not significant;
The percentage of RF positive patients did not differ in the various groups: 70%, 61%
and 61% in the Failures, Responders and Continued Infliximab Treatment respectively.
discussion
The secondary analysis of patients randomized to the fourth arm of the BeSt study demonstrate the potential of initial therapy with infliximab plus MTX to induce a du- rable low level of disease activity in patients with newly diagnosed RA. These patients did not receive corticosteroids besides intra-articular administration when necessary.
The BeSt study represents the first protocol where decisions about dose increase and decrease or discontinuation of infliximab are dictated by DAS calculations before every infusion.
The overall degree of clinical response in this population was similar to previous stu- dies of treatment with infliximab plus MTX in early RA(6-8). Remarkably, in 67 out of 77 (87%) patients who initially achieved a good response (DAS ≤2.4 for 6 months), this response lasted despite infliximab discontinuation and patients were able to taper MTX to a maintenance dose (discontinuation of MTX was not allowed in the pro- tocol). Indeed, the majority of these patients (40/67) achieved and retained clinical remission, DAS of less than or equal to 1.6, after 2 years follow up.
Figure 2: Progression of joint damage: mean change in SHS after 2 years of follow-up.
SHS= modified Sharp/van der Heijde score
0 1 2 3 4 5
Responder Continue d infliximab tre atment
Failure
de lta SHS Figure 2: Progression of joint damage: mean change in SHS after 2 years of follow-up.
SHS= modified Sharp/van der Heijde score
Ten of the 77 patients who discontinued infliximab experienced a disease flare after a median of 3.7 months and infliximab treatment was reinstated. The dosages of infliximab required to achieve a DAS less than or equal to 2.4 did not distinguish these patients from the patients with a persistent low disease activity despite infliximab discontinuation. Eight of the 10 patients who experienced a disease flare after discon- tinuation of infliximab achieved a DAS less than or equal to 2.4 again after reintroduc- tion of infliximab. This repeated effectiveness of infliximab is consistent with previous reports(14).
Interestingly, 42% (28/67) of Responders initially required infliximab dosages greater than 3 mg/kg to achieve a DAS less than or equal to 2.4 for at least 6 months. Long- term good clinical response seems not dependant on the dose needed to achieve a good clinical response but on the opportunity to accomplish this response.
The radiological results are comparable to those observed in the first study in early RA that compared initial treatment with infliximab plus MTX with MTX alone(8) and there are indications that the effect on joint damage may be drug specific(15). At the 2-year time-point, although the majority of Responders had discontinued infliximab for more than a year, the median progression in Sharp/van der Heijde score was small (1.5). Patients in the Failure group, who had been treated with infliximab longer and in higher dosages than the Responders, had significantly more progression of joint damage. This indicates that achieving low disease activity is more important in preventing radiological damage than continuation of infliximab therapy. Patients who required continued infliximab treatment achieved low disease activity, but it was not as persistent as for the Responders, and possibly as a consequence, they had more joint damage progression than the Responders, but less than the Failures. The fact that no significant differences were seen between the Continued Infliximab Treatment group and the other groups may be due to the sample size.
The results of this study can be seen as an extension of the growing evidence in recent years of the importance of effective treatment in the early phase of rheumatoid arthritis. It has been demonstrated that patients treated during this period have higher response rates to anti-rheumatic therapy than those who delay treatment(2-5) and experienced less joint damage(3). Studies comparing continuous MTX monotherapy with a TNF-blocking agent combined with MTX as initial therapy, have demonstra- ted better results from the combination therapies(5-8;16). In a study of 10 patients with early RA, Quinn et al(7) demonstrated for the first time a persistent good cli- nical response after discontinuation of infliximab in 7 out of these 10 patients after achieving low disease activity. The BeSt study now confirms these findings and shows that progression of joint damage is also adequately suppressed. In contrast, Buch et al(14) reported a relapse of disease activity in all 17 RA patients 13.5 to 15 weeks after discontinuation of infliximab. However, the patients participating in the ATTRACT study had a long disease duration and had failed on previous DMARD therapy. Long term follow up of patients in groups 1, 2 and 3 of the BeSt study, who have failed on conventional DMARDs and next received treatment with MTX plus infliximab, will de- monstrate whether these patients also will achieve low disease activity and successfully
patients in the initial infliximab plus MTX group of the BeSt study (56%) had a DAS less than or equal to 2.4 vs. 32% in the MTX monotherapy group(17). This could be the result of an early substantial reduction of the inflammatory process, after which
“minor” treatment is sufficient to suppress and slow down the disease process.
We conclude that initial treatment of patients with early, active RA with infliximab and MTX offers the opportunity to discontinue infliximab in the majority of patients once a repeated low DAS is achieved without flare of the disease. Even in most Responders low disease activity could be maintained with low dose methotrexate. Randomized controlled trials are needed to determine if continued treatment with infliximab results in a further reduction of joint damage progression once a good clinical response is achieved.
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