Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-{alpha} antibody compared with methotrexate in long-standing rheumatoid arthritis

P. Barrera1,, A. van der Maas1,2, A. E. van Ede1, B. A. L. M. Kiemeney2, R. F. J. M. Laan1, L. B. A. van de Putte1 and P. L. C. M. van Riel1

1 Department of Rheumatology and
2 Department of Epidemiology, University Medical Centre, Nijmegen, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-{alpha} (TNF-{alpha}) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response.

Methods. Patients with RA, enrolled in phase I trials with a human anti-TNF-{alpha} moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-{alpha} and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria.

Results. Sixty-one patients treated with anti-TNF-{alpha} moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-{alpha} group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12–0.6) uncorrected and 0.17 (0.06–0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-{alpha} group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-{alpha} group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-{alpha} group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-{alpha} dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75–6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)].

Conclusions. In patients with active, long-standing RA, blocking TNF-{alpha} is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-{alpha}. In contrast to MTX, the response to anti-TNF-{alpha} is not affected by previous disease-modifying anti-rheumatic drug history.

KEY WORDS: Arthritis, Rheumatoid drug therapy, Tumour necrosis factor antagonists and inhibitors, Methotrexate therapeutic use.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The specific neutralization of tumour necrosis factor-{alpha} (TNF-{alpha}) using monoclonal antibodies (moAb) and TNF receptor fusion proteins has proven successful in patients with rheumatoid arthritis (RA) [19]. Recent studies in patients who failed to respond to methotrexate (MTX), the most widely accepted second-line drug in RA, show a further improvement after combining this drug with TNF blocking agents [6, 1013]. Nonetheless, in some of these combination studies, the weekly dose of MTX at which patients were considered to be refractory was suboptimal. Until now, only one ‘head to head’ study has compared the effect of TNF neutralization, using the TNF receptor fusion protein etanercept, with MTX monotherapy in patients with early RA. The results of this study suggest that TNF neutralization is superior to MTX concerning both clinical improvement and reduction of radiological progression [14].

Since 1996, our department has been involved in clinical studies with adalimumab (D2E7, Knoll-BASF, Ludwigshafen, Germany) [710]. This compound is a fully human IgG1 moAb anti-TNF-{alpha} with high specificity for recombinant and natural TNF-{alpha} and generated with phage display techniques [15]. Placebo-controlled, multicentre studies show that repeated administration of this anti-TNF moAb is rapidly effective and well tolerated in patients with active RA [710]. Furthermore, this and other TNF blocking strategies seem to decrease radiological progression in RA [14, 16, 17]. Concomitant to the studies with adalimumab, our department designed and co-ordinated a phase III, 48-week, double-blind, placebo-controlled trial to study the effect of folate supplementation on the toxicity and efficacy of MTX monotherapy in patients with active RA [18].

The aforementioned trials with anti-TNF-{alpha} and MTX had very similar inclusion, exclusion, stop and response criteria. Furthermore, most patients included in these studies were scored by the same, blind assessors. In view of these similarities, we used the databases of both trials to compare the 48-week drug survival, efficacy and toxicity of repeated administration of this human anti-TNF moAb with MTX monotherapy in patients with active, long-standing RA. Secondary aims were to identify potential factors predictive for long-term response to anti-TNF and MTX therapy. Because folate supplementation could influence the toxicity and efficacy of MTX [1921], patients using concomitant folate supplementation were excluded from the present study.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The patients studied had RA according to the American College of Rheumatology criteria [22] and active disease, defined by a disease activity score (DAS) >3.0 [23]. The washout periods for the second-line drugs were 3 and 2 weeks for anti-TNF-{alpha} and MTX, respectively. Low-dose oral steroids (<10 mg/day) were allowed if they were kept constant 4 weeks prior to and during the study. Patients ever treated with MTX or under current therapy with folates, trimethroprim, probenecid, sulphonamides or allopurinol were excluded from the MTX study. Patients with a bodyweight >100 kg or having received intra-articular or intramuscular steroids within 1 month or biological agents within the previous year were excluded from therapy with anti-TNF. Common exclusion criteria were age <18 yr, pregnancy/breast feeding, severe medical conditions of abnormalities in liver or kidney function or in haematological parameters and history of alcohol or drug abuse.

Clinical efficacy during anti-TNF and MTX treatment was assessed using the DAS [23] and the European League Against Rheumatism (EULAR) response criteria [24]. Adverse events were recorded every 3 weeks and classified as mild, moderate or severe according to the judgement of the patient and the investigator.

Therapy with anti-TNF moAb started as a 6-week, double-blind, placebo-controlled study followed by an open-label phase. In the placebo-controlled part, the patients were randomly assigned to receive an initial dose of 0.5, 1, 3, 5 or 10 mg/kg of active drug or placebo. In the case of a lack of response, the same dose of anti-TNF moAb was administered at week 4. In the open phase, starting at week 6 from baseline, anti-TNF-{alpha} moAb was re-dosed biweekly unless a good EULAR response was still present at this time point. Patients with long-lasting responses were re-dosed only after losing their respondership status. In the low-dose groups (0.5 and 1 mg/kg anti-TNF), dose escalation up to 3 mg/kg was allowed in the case of a lack of a good response. All placebo-treated patients received anti-TNF in the open phase if they fulfilled the inclusion criteria. These patients were also analysed in this study, taking the real initiation of anti-TNF therapy as the baseline assessment. Anti-TNF therapy was withheld if the response criteria were not achieved after the initial 6 weeks or in the case of severe adverse events or lack of efficacy thereafter.

MTX was administered orally starting at a dose of 7.5 mg weekly. If a good response was not achieved, the protocol recommended an increase of the MTX dosage by 2.5 mg every 6 weeks, up to a maximum of 25 mg/week, until a good EULAR response was achieved. The drug was withheld in the case of severe/recurring adverse events or lack of efficacy. In the case of mild or moderate toxicities, the weekly dose of MTX was reduced by 2.5 mg or withheld until resolution, before MTX re-challenge. Hepatotoxicity was considered mild or moderate using an alanine transferase cut-off of < or >=3-fold the upper limit of normal, respectively. Mild or moderate events persisting or recurring after 3 weeks were handled as moderate or severe adverse events [18].

Outcome measures
Drug survival and dropout rates due to toxicity and lack of efficacy were calculated using cumulative individual data obtained at weeks 6, 12, 24, 36 and 48. Week 3 was also accounted for in the anti-TNF group.

The efficacies of anti-TNF and MTX were compared using several approaches. First, the numbers of patients who fulfilled the EULAR criteria for a good or moderate response at each visit were compared. The percentage of visits in which a given patient fulfilled the EULAR response criteria during the follow-up was also analysed. Furthermore, the time-integrated DAS course during both treatments was analysed using the area under the curve (DASAUC) from baseline to week 48.

Potential explanatory variables predictive for clinical response at week 48 were examined. These included age, sex, disease duration, rheumatoid factor, number of previous disease-modifying anti-rheumatic drugs (DMARDs) and DAS at baseline. For the anti-TNF group, the early clinical response, defined as the EULAR response achieved 2 weeks after the first dose, was also included in the analysis.

Statistical analysis
Drug survival analysis, corrected for differences in baseline values, was performed using a proportional hazard model (proc PHREG). After the 6-week placebo-controlled anti-TNF treatment, patients receiving verum and not achieving the EULAR response criteria were not allowed in the open phase, whereas those receiving placebo started anti-TNF therapy if they still fulfilled the inclusion criteria. Because this was not the case among MTX-treated patients, weeks 0–6 in both therapy groups were excluded from the survival analysis. Between-group comparisons were studied using Student's t-test, the Wilcoxon rank sum test and the {chi}2 test as appropriate. The difference in DASAUC between treatment groups was tested using analysis of covariance. Differences in efficacy and toxicity were studied using end-point analysis.

Logistic regression was used to identify factors predictive for response. The clinical response achieved at week 48 was used as the dependent variable. All analyses were performed using the SAS statistical package (SAS 6.04 PC version).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Baseline characteristics
The baseline characteristics of patients treated with anti-TNF-{alpha} (n=61) and MTX (n=137) are shown in Table 1Go. As expected from the inclusion criteria requiring no previous use of MTX, patients treated with this drug had a shorter disease duration and had used less second-line drugs in the past than those treated with anti-TNF (P=0.0001). Nevertheless, most patients had long-standing RA. In the group treated with anti-TNF, all but two patients had previously received MTX and 51% had to stop this therapy due to a lack of response. The DAS and Ritchie Articular Index at baseline were slightly higher in the anti-TNF group (Table 1Go). Other disease activity measurements at baseline were similar in both therapy groups, with the exception of the erythrocyte sedimentation rate (ESR), which was higher in the MTX group.


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TABLE 1.  Baseline patient characteristics as mean±S.D. unless otherwise stated

 
The anti-TNF-{alpha} group in this study represents all patients enrolled at our centre for participation in phase I trials with adalimumab (D2E7, Knoll-BASF). The characteristics of this patient subset were consistent with the whole study population [79] (data not shown). The patients receiving MTX participated in a phase III study comparing MTX alone with MTX and folic or folinic acid supplementation. In the latter, all patient subsets had similar baseline and efficacy characteristics, although folate supplementation significantly reduced MTX-related hepatotoxicity [18].

Drug survival and dropout rates
During the 48-week follow-up, 14 (23%) and 61 (45%) patients treated with anti-TNF-{alpha} and MTX, respectively, discontinued initial therapy (P<0.005). At 6 weeks from baseline, anti-TNF and MTX had been withdrawn in seven and five patients, respectively (Fig. 1Go).



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FIG. 1.  Drug survival curve for patients treated with a fully human anti-TNF moAb (D2E7; n=61) or MTX (n=137). Percentage of patients still on therapy on the y-axis. Time in weeks on the x-axis.

 
The study with anti-TNF required therapy cessation if no response was achieved during the 6-week placebo-controlled phase. Because this was not the case for the MTX group, this period was not considered in the proportional hazard analysis. The latter showed that the dropout risk between weeks 6 and 48 was much lower in the anti-TNF group than in the MTX group [relative risk (95% confidence interval): 0.28 (0.12–0.6)]. Correction for confounders (DAS at baseline and previous use of second-line anti-rheumatic drugs), yielded an even lower risk for dropout during anti-TNF therapy [relative risk (95% confidence interval): 0.17 (0.06–0.45)].

Whether other baseline demographic (age, sex), clinical (disease duration, rheumatoid factor positivity) and laboratory parameters influenced the dropout risk during anti-TNF therapy was also investigated. Only age seemed to have some influence as an effect modifier: the dropout risk was lower in younger patients than in older patients [relative risk (95% confidence interval): 0.12 (0.06–0.45) vs 0.21 (0.13–1.14), respectively] using the median as the cut-off point.

During the 48-week follow-up, dropout due to a lack of response occurred in seven (11%) patients receiving anti-TNF moAb and in only two patients (1.5%) treated with MTX. Dose escalation was performed in all patients receiving low-dose anti-TNF (0.5 and 1 mg/kg). In the group treated with MTX, 36.5% of the patients needed dose escalation to >15 mg/week and 51% had to withhold MTX temporarily due to toxicity. In the whole MTX group, the mean weekly dose at week 48 was 2-fold the initial dose (mean±S.D.=14.5±5.8 mg/week).

Adverse events were the reason to withhold therapy in seven (11%) and 52 (38%) patients treated with anti-TNF and MTX, respectively. Three patients in the anti-TNF group dropped from the study because of peri-infusional allergic reactions. Two patients developed a chronic skin rash and one of them refused further follow-up. In two additional patients, anti-TNF was withdrawn due to reasons considered not related to TNF neutralization. These consisted of mood disturbances and fear of malignancies (n=1) and lethal respiratory insufficiency at week 46 in a patient with severe chronic obstructive pulmonary disease. Severe or relapsing toxicities resulting in MTX discontinuation consisted of hepatotoxicity and gastrointestinal complaints in 35 and nine patients, respectively. Other adverse events requiring MTX withdrawal were rare (Table 2Go). MTX was discontinued in nine (6.6%) patients due to a refusal to co-operate or protocol violation.


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TABLE 2.  Adverse events during anti-TNF and MTX therapy. Data are expressed as number of patients (%) unless otherwise stated

 

Clinical response
The percentages of patients who fulfilled the criteria for a good or moderate response at each visit are shown in Fig. 2Go. As shown, 49 and 8% of the patients achieved the EULAR criteria for moderate and good responses, respectively, after the first administration of anti-TNF moAb. In the MTX group, 30 and 2% of the patients achieved moderate and good responses after 6 weeks of therapy. Considering good and moderate responses together, maximal response percentages were achieved at week 12 for the anti-TNF group (96% responders) and at approximately week 24 for the MTX group (63% responders). The percentages of moderate responders with both therapies showed a plateau at week 12, whereas the percentages of good responders increased steadily during the study, reaching a maximum of 36 and 33% with anti-TNF and MTX, respectively, at week 48. The numbers of moderate and good responders were significantly higher in the anti-TNF group than in the MTX group at all visits. The percentage of visits in which a given patient showed a good or moderate response was also higher in the anti-TNF group than in the MTX group [median (p25–p75): 83% (50–100) vs 40% (20–60), respectively].



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FIG. 2.  Clinical response in patients treated with human anti-TNF moAb (D2E7; n=61) or MTX (n=137) monotherapy. Percentages of good and moderate responders (open and solid symbols, respectively) according to the EULAR criteria. Time in weeks on the x-axis. MTX and D2E7 are represented as triangles and boxes, respectively. {blacksquare}, {square}, anti-TNF therapy; {triangleup}, MTX.

 
During the 48-week follow-up, the DAS showed a progressive decline with both therapies, which was most pronounced in the first 6 months (Fig. 3Go). The uncorrected DASAUC in the anti-TNF group was lower than in the MTX group, but this did not reach statistical significance [mean (95% confidence interval): 167 (153–181) vs 182 (173–192)]. The analysis of covariance showed that the number of previous second-line drugs and the DAS at baseline were the only confounding factors. After correcting for those factors, the DASAUC was significantly lower in the anti-TNF group than in the MTX group (P=0.001).



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FIG. 3.  Course of the DAS during 48 weeks of therapy with anti-TNF (n=61) or MTX (n=137) monotherapy. DAS on the y-axis. Time in weeks on the x-axis.

 
Apart from the DAS, the swollen joint count, the Ritchie score and the subjective assessments for pain and general health showed more marked improvement during anti-TNF therapy (Table 3Go).


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TABLE 3.  Changes in clinical and laboratory parameters of disease activity. Data are expressed as absolute changes (week 48—baseline) and as AUCweek 0–week 48 [median (p25 to p75)]

 

Factors predictive for response
With a single exception for each agent, most demographic, clinical and laboratory variables examined were not found to be predictive for the clinical response to anti-TNF or MTX therapy at week 48. The response after the first anti-TNF dose was positively related to the chance of a prolonged response, although this did not reach statistical significance [relative risk (95% confidence interval): 2.0 (0.75–6.0)]. In patients treated with MTX, the only variable related to a prolonged clinical response was the number of previous second-line anti-rheumatic drugs [relative risk (95% confidence interval): 0.71 (0.57–0.88)]. The latter was not the case for anti-TNF.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of our open comparison across trials show that repeated administration of a human anti-TNF-{alpha} moAb has a better drug survival curve and is more effective than MTX monotherapy in patients with active long-standing RA. These studies were not primarily set up to compare anti-TNF and MTX monotherapy, although their inclusion, exclusion and response criteria were very similar. Some differences, such as the inclusion of MTX-naive patients in the MTX study, could have resulted in a selection of patients with short disease duration and less severe RA. On the other hand, the relatively low initial dosage of MTX and the lack of folate supplementation, which reduces hepatotoxicity [18], may have been a disadvantage for the MTX group and not representative of daily clinical practice. Furthermore, the dosing of MTX occurred on a fixed schedule, whereas in the open phase, anti-TNF was re-dosed only in the case of flare. Taking these limitations into account, we consider that our study can provide useful information about the value of TNF neutralization in comparison with MTX.

The 48-week dropout rates for the anti-TNF and MTX groups were 23 and 45%, respectively. The results of the survival analysis, both uncorrected and corrected for confounders, showed that the relative risk for dropout was significantly lower in patients receiving anti-TNF [relative risk (95% confidence interval): 0.28 (0.12–0.61) and 0.17 (0.06–0.45), respectively].

The proportions of patients who discontinued therapy due to adverse events and lack of efficacy were different with both therapies. Toxicity leading to dropout was less frequent in patients treated with anti-TNF than in those receiving MTX monotherapy (11 vs 38%, respectively). Peri-infusional allergic reactions and skin rash (n=5) were the only toxicities related to anti-TNF therapy which required drug withdrawal. No systemic lupus erythematosus-like reactions or malignancies were observed in this study. Conversely, hepatotoxicity was the most common event forcing withdrawal of MTX and explained 67% of the total dropout with this drug.

Only 11% of patients treated with anti-TNF withdrew due to a lack of efficacy in our study. Similar percentages of non-responders have been reported in other long-term studies using TNF neutralization in RA [8, 1214] and these compare favourably with most other currently available strategies.

Previous literature shows that toxicity, rather than a lack of efficacy, is the main limiting factor for MTX therapy in RA [2527]. The 48-week withdrawal rate due to a lack of efficacy in this study was 1.5% and this is rather low as compared with previous studies (5–15%) [14, 2830]. This is probably explained by the relatively slow dose escalation schedule allowed in the case of MTX inefficacy in our study.

Concerning clinical efficacy, our results show that anti-TNF has a very short lag time to response. A total of 57% of patients fulfilled the EULAR response criteria 2 weeks after the first administration of adalimumab and the maximal response percentage was reached at week 12. These observations are corroborated by results from multicentre trials using either the same compound [79] or other approaches to TNF neutralization [1, 4, 5, 12, 13].

Based on previous studies with this and other TNF blocking agents and on the world-wide experience with MTX therapy in RA [28, 3134], the effect of anti-TNF was a priori expected to occur earlier than that of MTX. To our surprise, the superiority of anti-TNF therapy was not only apparent early in the study, but at all visits throughout the 48-week follow-up. This was considered of relevance as the longer disease duration and the protracted history of second-line anti-rheumatic drugs pointed to a more refractory disease in the anti-TNF group. Most patients receiving this therapy had in fact already used MTX in the past and at least 51% had been refractory to this drug. Re-dosing of anti-TNF was only allowed after the disease activity (DAS) increased and the initial clinical response (according to EULAR) was lost. This schedule meant that the patients treated with anti-TNF had to have some disease flare between the doses and this was not the case for the MTX group.

Our data show, therefore, that, despite the more refractory disease and the relatively low frequency of anti-TNF dosing in this study, this therapy is rapidly effective and clinically superior to MTX in patients with active, long-lasting RA. Interestingly, the therapy also slows down the radiological progression even at late stages of the disease [16]. Similar results have been recently reported in patients refractory to MTX treated with MTX in combination with the chimeric anti-TNF moAb infliximab [17] and in a trial of MTX vs the TNF receptor fusion protein etanercept in early RA [14].

MTX combined with TNF neutralization is more effective than MTX alone. Such a synergistic effect has been demonstrated in studies with the same human anti-TNF moAb used in this study [10] and also with infliximab [6, 13] and etanercept [12]. The MTX dose used in these combination studies has ranged from 10 to 25 mg/week and only two studies mention the use of standard folate supplementation to minimize MTX toxicity [12, 14]. The efficacy of MTX is, to a certain extent, dose related [35, 36] and, for present standards, the MTX dose used in this and other studies might have been suboptimal. Higher maintenance doses of MTX, without increased toxicity or losing clinical efficacy, can be achieved using folate supplementation [18]. Additional manoeuvres to optimize MTX therapy in patients refractory to the latter include combinations with other second-line drugs [35, 37, 38]. Further studies comparing TNF neutralization with optimized current strategies, including MTX combined with other DMARDs and newer drugs that also slow the rate of radiological progression, would be needed to establish the adequate place of TNF neutralization among currently available therapies.

An interesting trend in our study was the fact that the EULAR response observed after the first anti-TNF administration increased by 2-fold the chance of a long-term response. This observation sustains the updated consensus on TNF blocking agents for RA [39] which recommends discontinuing therapy in the case of a lack of an early response. Moreover, we found a lower dropout risk among younger patients and similar findings have been recently reported in a subgroup analysis of patients treated with MTX and infliximab [40]. If the first observation is confirmed in larger studies, the assessment of clinical response criteria within some weeks after the initiation of anti-TNF could be used to improve the cost-effectiveness of this therapy. Of interest is also the fact that the number of previous DMARDs was inversely related to the chance of a long-term response to MTX [relative risk (95% confidence interval): 0.71 (0.57–0.88)], but this was not the case for anti-TNF. This observation corroborates previous studies showing that disease duration and prior DMARD use are inversely related to the likelihood of response to DMARDs [41, 42], although this does not seem to be the case for TNF blocking therapies.

This open study shows that repeated administration of a human anti-TNF moAb has a better drug survival profile, a shorter lag time to response and is more effective than MTX monotherapy in patients with active, long-standing RA. Our study does not obviate the need for randomized clinical trials to establish the place and correct timing of TNF neutralization among currently available therapies. Phase III, double-blind trials comparing the efficacy of this human monoclonal anti-TNF with MTX in early RA are ongoing.


    Acknowledgments
 
We are indebted to Martin A. van't Hoff, Albert Reintjes and Theo de Boo from the Statistics Department of the University of Nijmegen. The clinical studies with this human anti-TNF-{alpha} antagonist and MTX were supported by Knoll-BASF and by the Ontwikkelingsgeneeskunde, Ziekenfondsraad, The Netherlands (grant no. 95–016), respectively.


    Notes
 
Correspondence to: P. Barrera, Department of Rheumatology, University Medical Centre, Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 1 May 2001; Accepted 19 October 2001