Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-{alpha}

A. A. den Broeder, M. C. W. Creemers, A. M. van Gestel and P. L. C. M. van Riel

Department of Rheumatology, University Medical Center St Radboud, Nijmegen, PO Box 9101, 6500 HB, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Anti-tumour necrosis factor {alpha} (TNF-{alpha}) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis (RA), and on theoretical grounds large differences in the effective dose between patients can be expected. Together with the high costs, these differences warrant new approaches to the way patients are dosed.

Methods. We used the Disease Activity Score (DAS28), a composite disease activity index, to titrate the dose of anti-TNF-{alpha} (adalimumab, D2E7; Knoll) in 21 patients with low disease activity in an open extension study lasting 40 weeks. The dose of anti-TNF-{alpha} was reduced stepwise and dosing intervals were kept stable. Disease activity and flares were assessed using the DAS28. Patients who flared received the previous effective dose.

Results. Dose reduction was accomplished in 15 patients. The total amount of anti-TNF-{alpha} given to the patients was reduced by 67%. At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA.

Conclusion. Dose titration of anti-TNF-{alpha} treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy. This approach will save costs and possibly prevent long-term side-effects.

KEY WORDS: DAS28, Anti-TNF-{alpha}, Dose titration, RA, Adalimumab, Infliximab.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Treatment of rheumatoid arthritis (RA) has traditionally been centred round the use of disease-modifying anti-rheumatic drugs (DMARDs) as the main agents to reduce disease activity and influence the course of the disease. Although effective, no single agent from this group is able to control the disease fully in the majority of patients. Furthermore, the use of DMARDs is often limited by toxicity, leading to dose adjustments or cessation of therapy [1]. In recent years, increased knowledge of the mechanism underlying the inflammation seen in RA has led to the development of new agents. In contrast to conventional DMARDs, which have mostly been discovered empirically, these so-called biologicals have been designed specifically to block either the action of immune cells or the cytokines produced by these cells [2]. A number of these agents have been developed and tested clinically, the most promising being the agents targeting tumour necrosis factor {alpha} (TNF-{alpha}). These latter agents are expected to change current therapeutic strategies dramatically in order to control RA, as a result of their impressive efficacy and low toxicity profile, although their exact place in the treatment of RA has yet to be established [3].

TNF-{alpha} blocking agents have unique properties that distinguish them from conventional DMARDs. First, clinical effects occur within days to weeks, whereas with DMARDs responses are seen no earlier than 4 weeks to 3 months. Secondly, because of dose-dependent toxicity it is often not possible for DMARDs to be given at the dose that is necessary to obtain optimal clinical efficacy. For anti-TNF-{alpha} agents in general, no dose-dependent toxicity has been found, although a study with infliximab suggested more upper airway infections in the higher dose groups [47]. A third important difference is the expected large variation between patients regarding the optimal dose of anti-TNF-{alpha}. For conventional DMARDs the difference between the lowest and highest effective doses does not often exceed one order of magnitude; for example, doses of methotrexate (MTX) range from 5 to 30 mg/week, a six-fold difference. In vivo levels of cytokines often differ by one or several orders of magnitude between RA patients [8]. TNF-{alpha} blocking agents bind TNF-{alpha} in a fixed ratio [9], and it is therefore conceivable that there are large differences in the required doses of these agents. For obvious reasons, in randomized controlled trials a restricted number of fixed doses is being studied. The use of standard dosing schedules in daily clinical practice will, however, result in gross under- and/or overtreatment. Prevention of overtreatment might reduce the long-term side-effects, as the first cases of diseases associated with impaired immune response have been reported already [10].

Tailoring treatment to the individual needs of the patient will also reduce the high costs that are another hallmark of TNF-{alpha} blocking agents compared with traditional DMARDs. The first TNF-{alpha} blocking agent that has been approved for the treatment of RA (etanercept) is over 200 times more expensive than, for example, MTX (etanercept 25 mg twice a week, 14 000 euros/yr vs 60 euros/yr for MTX 15 mg/week).

To titrate the dose of anti-TNF-{alpha} according to disease activity, it is necessary to monitor disease activity continuously. The Disease Activity Score (DAS28) is a continuous composite index for measuring disease activity in RA, which has been well documented and validated [11, 12].

In order to test the hypotheses that there is a large difference between patients in the required dose of anti-TNF-{alpha} and that titration of anti-TNF-{alpha} treatment is feasible, a dose titration regimen using the DAS28 in patients with RA, treated with anti-TNF-{alpha}, was studied.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with RA who were being treated in a clinical trial with anti-TNF-{alpha} in our centre were studied for 40 weeks. Patients had originally been enrolled in a 6 week phase I study. The entry criteria for the original study included RA fulfilling the American Rheumatism Association criteria and high disease activity, measured using the DAS. Patients had subsequently been treated in an extension study for 2 yr with anti-TNF-{alpha} (adalimumab, D2E7; Knoll, Ludwigshafen, Germany) administered intravenously. During the second year of this extension study, the patients had been treated with a fixed dose of 3.0 mg/kg. The dosing interval was either 2 or 4 weeks depending on the clinical effect in the first year of anti-TNF-{alpha} treatment, but was fixed for each patient and remained unchanged in the second year and during the present study. All patients were responding to treatment and showed a stable level of relatively low disease activity in the year preceding this study. Treatment with other DMARDs was not allowed. Steroids equivalent to up to 10 mg/day prednisone were accepted and the dose was kept stable during the study.

Patients were seen every 8 weeks to evaluate disease activity and toxicity. Disease activity was measured using the DAS28 [11]. This disease activity index ranges from 0 to 10 and includes the 28 tender and swollen joint counts, the erythrocyte sedimentation rate (ESR) (Westergren, mm/h) and the patient's assessment of disease activity measured with a visual analogue scale (100 mm). DAS28 >5.1 means the patient has high disease activity and DAS28 <3.2 means that disease activity is low. A change in DAS28 of >0.6 constitutes a change greater than the measurement error of the DAS28. A change in DAS28 of >1.2 (twice the measurement error) is a clinically significant change in the DAS28. A disease flare was defined using a reversed version of the EULAR criteria for response [12]. The criterion for a disease flare was an increase in DAS28 of >1.2 or an increase in DAS28 of 0.6–1.2 if this resulted in DAS28 >5.1. The DAS28 is calculated as follows: DAS28=0.56{surd}tender 28+0.28{surd}swollen 28+0.70 ln ESR+0.014General Health.

Doses of anti-TNF-{alpha} were decreased stepwise at every 8-weekly visit from 3.0 to 1.0, 0.5 and eventually to 0.25 mg/kg. If a flare of the disease occurred, the dose of anti-TNF-{alpha} was increased one step to the previous dose of anti-TNF-{alpha}. Between the 8-weekly visits, patients visited the out-patient clinic every 2 or 4 weeks for intravenous administration of anti-TNF-{alpha}. A DAS28 was assessed during these drug administration visits only if the patient reported a disease flare. In this way, a prolonged flare of RA was prevented.

The minimal individual dose required to sustain the response was assessed using this protocol. The total weekly dose for each patient was calculated taking into account the different dosing intervals. A paired t-test was used to test DAS28 values at baseline and at the end of the study.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-one patients were included in this study. Patient characteristics are shown in Table 1Go. At the start of the study the mean DAS28 was 3.5 (range 1.4–4.7). None of the patients had a high level of disease activity (DAS28 >5.1) at the start of the study.


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TABLE 1.  Baseline characteristics of patients (n=21)

 
In Fig. 1Go the use of the DAS28 for titration of therapy is shown for one patient. At week 0, the dose of anti-TNF-{alpha} was 3.0 mg/kg. This was lowered to 1.0 mg/kg at week 8. At week 16, the dose was further lowered to 0.5 mg/kg. This dose reduction resulted, after 2 weeks, in a flare with an increase in DAS28 of >1.2. The dose of anti-TNF-{alpha} was increased again to 1.0 mg/kg and remained unchanged for the rest of the study. The DAS28 quickly returned to baseline level.



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FIG. 1.  DAS28 course and anti-TNF-{alpha} dose titration in one patient. After a decrease in dose of anti-TNF-{alpha} from 3.0 to 1.0 and subsequently to 0.5 mg/kg, a flare of the disease occurred, reflected in an increase in DAS28. After the dose of anti-TNF-{alpha} had been increased to 1.0 mg/kg, the DAS28 returned to the previous low level.

 
The results of the dose titration are shown in Fig. 2Go. Six out of 21 patients were placed back on the original dose of 3.0 mg/kg after flaring on 1.0 mg/kg whereas nine, three and three patients respectively reached a dose of 1.0, 0.5 and 0.25 mg/kg. Required weekly doses of anti-TNF-{alpha} ranged from 4.1 to 130 mg. The differences between the weekly required absolute doses of anti-TNF-{alpha} were caused by differences in dose (3.0–0.25 mg/kg, factor=12), differences in dosing interval (every 2 or 4 weeks, factor=2) and differences in bodyweight (53–90, factor=1.7). As a result of this dose reduction, the median of the calculated weekly dose of anti-TNF-{alpha} administered to these patients was reduced by 67% from 97.5 mg/week (range 46.3–135) to 32.5 mg/week (range 4.1–130). One protocol violation was noted: in one patient the dose was increased while the increase in disease activity did not meet the criteria for a disease flare, with an increase in DAS28 of 0.83 to reach 4.84.



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FIG. 2.  Results of the anti-TNF-{alpha} dose titration. The total weekly doses of the individual patients (n=21) before and after the dose titration phase are shown in mg/week. Medians are shown as a horizontal bar. The differences between individual patients before the dose titration study are caused by differences in dosing interval (every 2 or 4 weeks) and differences in body weight.

 
Eighteen patients flared during the study, with a mean increase in DAS28 of 1.3. Eight of these patients reported a flare between the regular 8-weekly evaluations, and the other 10 patients had their dose adjusted at the regular evaluation. Three patients did not experience a flare even on the lowest dose of 0.25 mg/kg anti-TNF-{alpha}. At the end of the study, one patient had a DAS28 that was >1.2 higher than the DAS28 at baseline. No patients dropped out during the study because of a persistent increase in disease activity. The mean DAS28 at the end of the study was 3.8 (range 2.0–5.1), which was somewhat higher than, but not significantly different from, the DAS28 of 3.5 (range 1.4–4.7) at the start of the study.

DAS28 <2.0 (compatible with remission) was seen in 20 of the 126 visits (16%). Seven of the 21 patients had DAS28 <2.0 at any time, whereas the other 14 patients never reached a remission level. One patient had DAS28 <2.0 at all visits; the other six patients had higher DAS28 values between visits.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To our knowledge, this is the first report of the use of a dose titration regimen to tailor anti-TNF-{alpha} treatment in individual patients. Although our study included only a limited number of patients, it demonstrates the principle of dose titration and the advantages of this approach compared with the common ‘one size fits all’ standard dosing schemes.

The importance of monitoring disease activity in daily clinical practice has been recognized recently and several monitoring and clinical quality management protocols are currently under investigation [1315]. To implement a dose titration regimen, measurement of the actual disease activity is necessary, preferably on a continuous scale. Improvement criteria such as those of the American College of Rheumatology (ACR) [16] and Paulus et al. [17] are not suitable for this purpose as these criteria define response as a relative improvement, disregarding the actual disease activity. This hampers the use of these criteria in daily clinical practice, although these criteria have shown their value in randomized clinical trials. The same holds true for adaptations of the ACR response criteria, the ACR 50% and 70% criteria.

In our study, the DAS28 with four variables was used to measure disease activity. A DAS28 using only three variables (‘patient's assessment of disease activity’ is omitted) has also been developed. This was done to allow a DAS28 to be calculated in data sets that omit this variable. Although the impact of the patient's assessment of disease activity on the resulting DAS28 is not very large, when conducting a prospective study it is advisable to include this variable as it provides information that is otherwise lost.

The use of the DAS28 is feasible and time-effective using a preprogrammed calculator, spreadsheet or web-based calculator (www.das-score.nl). One should be aware, however, that the cut-off levels for high and low disease activity mentioned in this report are calculated in terms of the DAS28. The original DAS, which is based on the Ritchie Articular index for tender joints and the 44 swollen joint count, uses 3.7 as the cut-off level for high disease activity and 2.4 for low disease activity. The measurement error is the same for both the DAS and the DAS28.

In spite of the relatively small number of patients, we found marked variation in the required dose of anti-TNF-{alpha}. Required doses ranged from 4.1 to 130 mg/week. Using the titration regimen described above, the median weekly amount of anti-TNF-{alpha} given to these patients could be lowered by 67%, from 97.5 to 32.5 mg/week. As no smaller dose steps than 0.25 mg/kg were included, one could speculate that even further reduction is possible for individual patients. This is supported by the remarkably long duration of response seen in some patients after only one administration of anti-TNF-{alpha}, documented for both D2E7 (up to 14 weeks EULAR response) and infliximab (up to approximately 18 weeks Paulus 20 response) [18, 19]. Because the patients in this study had had a stable and low disease activity on 3.0 mg/kg for 1 yr, it was not necessary to include a higher dose of anti-TNF-{alpha} in this titration regimen.

The other possible approach to dose titration is time-interval titration. In our centre a group of 12 patients with exceptionally refractory RA and high baseline disease activity (median number of different DMARDs used=6, mean DAS28 at baseline=6.2) have been treated with infliximab infusions using a time-titration regimen based on the same flare criteria as that used in the present study. Infusions were delayed until a disease flare occurred. The new time interval was based on the time to flare derived from the last infusion, with a minimum interval of 4 weeks and a maximum of 16 weeks. Even in this selected group of patients with severe RA, substantial differences in the dosing interval required could be demonstrated (median interval 5.1 weeks, range 4–7 weeks). The calculated weekly doses required were between 24 and 76 mg/week (factor=3.2). Some patients might have benefited from an even shorter dosing interval, but this was not allowed by the study protocol.

A drawback of step-down dose titration is the inevitable disease flare in the titration phase. Eighteen out of 21 patients experienced a flare of the disease, but the mean DAS28 after the dose titration phase was not significantly higher than the DAS28 at the start of the study. Moreover, no patients dropped out of the study because of a persistent flare. However, it should be noted that if there was an increase in disease activity the dose of anti-TNF-{alpha} could be adjusted at a drug administration visit (every 2 or 4 weeks). In this way, prolonged deterioration of the RA was prevented.

In conclusion, dose titration of anti-TNF-{alpha} treatment using the DAS28 is feasible and leads to a substantial reduction in median dose while clinical efficacy is maintained. There is marked variation in the individual dose of anti-TNF-{alpha} needed to maintain clinical efficacy. This approach will save costs and may prevent long-term side-effects.


    Notes
 
Correspondence to: M. C. W. Creemers. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 8 May 2001; Accepted 28 December 2001