A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks can be effective: a Belgian prospective study

P. Durez, F. Van den Bosch1, L. Corluy2, E. M. Veys1, L. De Clerck3, A. Peretz4, M. Malaise5, J.-P. Devogelaer, N. Vastesaeger6, A. Geldhof7 and R. Westhovens2

Rheumatology Departments, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1 University Hospital R. U. Ghent, 2 University Hospitals K. U. Leuven, 3 University Hospital Antwerp, University of Antwerp, 4 University Hospital Brugmann, Brussels, 5 University Hospital Liège, 6 Schering Plough, Belgium, 7 Centocor BV, Leiden, Belgium.

Corresponding author: R. Westhovens, Rheumatology Department, UZ Gasthuisberg, Katholieke Universiteit Leuven, Belgium. E-mail: rene.westhovens{at}uz.kuleuven.ac.be


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To analyse the effect of a dose increase in patients with severe rheumatoid arthritis (RA) with insufficient clinical response to 3 mg/kg infliximab every 8 weeks.

Methods. Patients suffering from active refractory RA despite methotrexate, were treated with i.v. infusions of infliximab (3 mg/kg) on week 0, 2, 6 and every 8 weeks thereafter. Based on the clinical judgement at week 22, patients received a dose increase of 100 mg from week 30 on. The American College of Rheumatology (ACR) core set for disease activity measures was regularly assessed.

Results. Five hundred and eleven RA patients were included. At week 22, 61.4, 34 and 14.1% of all patients met ACR 20, ACR 50 and ACR 70 criteria, respectively, and 6.1% of patients were in remission. A low swollen joint count at baseline was correlated with improvement at week 22 for ACR 20 (P<0.06), ACR 50 (P<0.06) and ACR 70 (P<0.005). The change in HAQ score between weeks 0 and 22 was predictive for response at week 54 (P<0.01). The dose of infliximab was increased by 100 mg in 22% of the patients. Most baseline values of patients requiring dose increase were higher (P ≤ 0.001) than the baseline values of the remaining patients. Increasing the dose of infliximab by one vial from week 30 on could circumvent the partial loss of response in these patients.

Conclusion. Infliximab use in this large out-patient cohort resulted in a significant clinical improvement. A subgroup that partially lost response during the first 22 weeks could regain response by adding 100 mg of infliximab to the subsequent doses. Due to the current study design, however, a regression to the mean like effect could not be ruled out.

KEY WORDS: Rheumatoid arthritis, Infliximab, Dose adjustment, ACR core set


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Infliximab is highly effective in the majority of rheumatoid arthritis (RA) patients in clinical trials. In the ATTRACT trial [1], where patients were forced to stay on a single dose regimen, a dose of 3 mg/kg every 8 weeks, which became the proposed standard dose, had a tendency to be less effective than either a higher dose of 10 mg/kg every 8 weeks or a shorter perfusion interval (3 mg/kg every 4 weeks).

Not taking into account discussions on which measurement of response is relevant in daily practice [2], physicians feel that some patients could benefit from a higher infliximab dose.

We therefore evaluated the efficacy and safety of an increase in infliximab dose in RA patients in an early access protocol before the drug was reimbursed. We also studied the potential predictors for the need for such a dose increase as well as predictors of the effect of a higher dose.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients aged between 18 and 80 yr fulfilling American College of Rheumatology (ACR) criteria for RA [3], suffering from active disease despite treatment with methotrexate (MTX) at a weekly dose of 15 mg (at least 10 mg in the case of poor tolerance) were studied. MTX was continued. There was only a difference in inclusion criteria for this study compared with the later decided reimbursement criteria for number of swollen joints (six in the present study, eight for reimbursement criteria) and for Health Assessment Questionnaire (HAQ) (>25th percentile in reimbursement criteria, no requirement in present study).

Infliximab was administered at week 0, 2, 6 and every 8 weeks thereafter at a dose of 3 mg/kg. Throughout the first 22 weeks MTX, non-steroidal anti-inflammatory drugs and steroid dose were stable. Based on the clinical judgement of the treating rheumatologist at week 22, the study design permitted a dose increase of one vial (100 mg) of infliximab from week 30 onwards. We decided on a dose increase of just one vial every 8 weeks and not a weight-adjusted increase or a shortening of the infusion interval, mainly for practical and budgetary reasons.

The ACR core set response score [4] and the DAS28 score [5] were evaluated at the same time points before the infliximab infusion, and adverse events were tracked into the case report form.

Statistics were analysed using an unpaired Student's t-test (Mann–Whitney U-test). P values for the ACR 20% and 50% response rates were calculated using Fisher's exact test. A logistic regression model (Epsilon Group, Charlottesville, VA 22901, USA) was used to predict a discrete outcome (ACR 20, ACR 50, ACR 70) from a set of parametric variables that are either continuous or discrete or a mix and to describe the importance of ACR core set predictors.

Ethical approval and individual informed consent were obtained for the study and every individual patient.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Baseline characteristics of the 511 refractory RA patients studied are indicated in Table 1.


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TABLE 1. Baseline characteristics by treatment group

 
At week 22, 61.4, 34 and 14.1% of patients met ACR 20, ACR 50 and ACR 70 criteria, respectively. By 62 weeks, these percentages further increased to 66.1, 43.2 and 22.8%. The criteria for remission were fulfilled at 22 weeks by 6.1% of patients; at 62 weeks the figure was 7% of patients. Using a logistic regression model, we were able to substantiate that a low swollen joint count (SJC) at baseline correlated with ACR 20 (P<0.06), ACR 50 (P<0.06) and ACR 70 (P<0.005) responses at week 22. A change or improvement in HAQ from baseline to week 22 was significantly correlated with improvement in ACR 20 (P<0.004) and ACR 50 (P<0.0001) at week 54.

For 106 patients (22%) it was decided that the clinical condition required a dose increase. Interestingly, 34.2% of patients qualifying for infliximab dose adjustment were at least ACR 20 responders. In a representative cohort of 241/511 patients, clinical response was also compared with DAS28 (good + moderate) response criteria [5]. Out of 175 clinical responders, 82% of patients were DAS28 responders. From 66 patients considered for dose increase, 53% had a DAS28 response.

For the patients who received a dose increase, most baseline values were significantly higher compared with patients continuing on a stable dose (Table 1). Both groups showed a comparable improvement during the infliximab induction phase but a divergence between weeks 6 and 22.

Between weeks 30 and 54, patients remaining on 3 mg/kg every 8 weeks increased respectively their proportion of ACR 20 and ACR 50 responses from 60 to 74% and 37 to 50% (Fig. 1). In comparison, ACR 20 increased from 34% at week 30 to 61% at week 54 and ACR 50 response rates increased from 12 to 25% between weeks 30 and 54 in the patient population that received a dose increase of 100 mg. At week 62, patients on dose increase therapy reached nearly the same ACR 20 response as the group on the stable dose.



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FIG. 1. Effect on the American College of Rheumatology (ACR) 20% response rates up to week 62. The arrow refers to the start of a dose increase.

 
In total, 164 serious adverse events (SAEs) were reported. Three patients from the constant dose group died (leucoencephalopathy, pneumonia and unknown cause). One hundred and thirty-four SAEs were observed in the stable dose group and 30 in the dose increase group. Infections were the leading cause of events (34% of SAEs) with 44 and 11 events reported in the stable dose and dose increase group, respectively. Other SAEs that were reported were malignancies (n = 12), cardiovascular events (n = 12), and hypersensitivity (n = 9).


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our study confirmed the efficacy of infliximab in a large cohort of refractory RA patients, and the data obtained at week 22 are well in line with the standard dose of 3 mg/kg in the ATTRACT trial [1].

In ATTRACT, the ACR response in patients treated with 3 mg/kg every 8 weeks had a tendency to be lower than responses obtained with a higher dose or a shorter perfusion interval. This difference was only significant with regard to the ACR 50 response criteria. Pharmacokinetic analysis of serum samples from the ATTRACT study shows that the serum level of infliximab is statistically more frequently undetectable in patients treated with 3 mg/kg every 8 weeks compared with patients treated with a higher dose (10 mg/kg) or a shorter treatment interval (every 4 weeks). More patients with detectable levels (>0.1 µg/ml) of serum infliximab pre-infusion show ACR responses as compared with patients without detectable infliximab levels. The authors suggest that shortening of the dose interval would be preferable to increasing dose at a constant interval [6].

The unique design of the present study has important differences from the ATTRACT trial. It studied an increase in the dose of infliximab upon clinical need rather than using outcome criteria as in clinical trials, which is probably more relevant in daily practice. This resulted in a decision to increase the infliximab dose by 100 mg in 22% of patients, improving the clinical response. This percentage is comparable to the percentage of patients with undetectable infliximab serum through levels reported by St Clair et al. [6].

In a recent report about dosage rates and patterns of compliance with anti-TNF treatment in the United States, Harley et al. [7] noted a final mean dosage of 382 mg (4.68 mg/kg), with 37% of patients receiving a dose increase. In our study, the final mean dosage was 232 mg compared with 310 mg (4.43 mg/kg) for patients who required a dose increase.

The clinical outcome of infliximab dose increase was also analysed in a small population of RA patients included in the STURE database [8]. Van Vollenhoven et al. [8] show that following dose increases better results were observed, such that the average DAS28, SJC and ACR-N improved and 18–36% of patients met formal response criteria. However, based on the modest nature of the improvements and on the observation that patients do improve after a period of worsening disease activity, irrespective of the treatment modality, the authors suggest that these findings might be explained by a regression-like effect.

Sidiropoulos et al. [9] also published a small study wherein 38 patients needed dose adjustment in the form of a shortening of dose interval to 6 weeks based on DAS responses. Increase in dose intensity led to a significant decrease in DAS, but only to a limited improvement in EULAR response.

The degree of response to infliximab is quite unpredictable. This report, however, shows that there is a subgroup of RA patients who partially lose the response seen after the induction therapy and who seemed to regain this response following administration of a dose increase. As opposed to the three previously mentioned observational reports, the prospective design of the study only allowed an increase at specific time points during the course of treatment. This timing of 22 to 30 weeks reflects the moment where the highest percentage of undetectable infliximab levels can be expected. Interestingly, the patients requiring dose adjustment have significantly higher disease activity at baseline. Despite the significant difference in baseline parameters, this higher disease activity could not be used to predict response to treatment. The change in HAQ score between baseline and week 22 was, however, significantly correlated with ACR response at week 54 and might be the assessment of choice to decide on dose adjustment.

Our results have the shortcoming of not being randomized and controlled. Therefore, we cannot rule out that the results are partially due to a regression towards the mean phenomenon, as has been previously suggested [8]. It is clearly shown, however, that the two groups are significantly different for all parameters at baseline. The mean increased dose patient clearly responds differently to treatment after week 6 compared with the mean constant dose patient, whereas the response to induction dose is almost identical. As such, from the moment the infusion interval increases the response to treatment seems to be partially lost. The increase in ACR 20 responders was 14% for the constant dose patients and 27% for the increased dose patients. Based on these arguments we think the overall improvement seen in patients who received an increased dose is more than a statistical phenomenon.

In our study we let an expert physician judge loss of response rather than use a judgement based on validated disease assessments. Outcome measures such as ACR 20 used in clinical trials are not necessarily an accurate reference in daily clinical practice [2]. Interestingly, 34.2% of the patients with insufficient response in our study fulfilled the ACR 20 response criteria. The importance of the clinical judgement is further highlighted by the difference in evolution of response between the two groups of patients from week 30 to week 62. Indeed, following clinical assessment by the rheumatologists, the response rates of both treatment groups again display a convergent evolution.

Safety updates of treatment with TNF{alpha} blockers were published recently [10–12]. With regard to safety issues, a limited dose increase as done in this study did not cause any increase in adverse events.

In conclusion, in RA patients with suboptimal response or loss of response to 3 mg/kg infliximab, the dose of infliximab can be increased above 3 mg/kg every 8 weeks by one single vial at each infusion. This limited dose increase appears to add clinical efficacy in 22% of patients in our study. Further randomized studies including the comparison of different infliximab dose escalation regimens to appropriate controls and pharmaco-economic objectives are needed to better define this subpopulation and to further analyse their long-term evolution.


    Acknowledgments
 
Schering-Plough (Belgium) kindly supported this investigator-initiated study. Thanks also to Freddy Cornillie, Ph.D. at Centocor BV, The Netherlands for his scientific advice and comments and to Fabienne Van Heuverbeke at DRC, Belgium who did an excellent job in monitoring this study.

P. Durez and R. Westhovens were consultants for Schering-Plough Belgium during this study. N. Vastesaeger is a Shering-Plough employee. A. Geldhof is an employee of Centocor BV. The other authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 15 July 2004; revised version accepted 22 October 2004.