Objectives: In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is frequently applied in clinical practice. Individual adjustment of infliximab treatment based on actual disease activity, instead of subjective clinical judgement, could prevent possible unwarranted dose escalation.
Methods: The infliximab dose of all patients with RA treated at our centre was decreased from 5 mg/kg to 3 mg/kg, leaving dosing intervals unaltered. Subsequently patients were followed for at least three infusions. At every visit, 28-joint Disease Activity Score (DAS28), infliximab serum trough levels and anti-infliximab antibody levels were assessed. Inversed European League Against Rheumatism (EULAR) criteria (flare criteria) were used as the endpoint.
Results: A total of 18 patients were included in the study. Mean (SD) DAS28 scores before dose reduction and after first and second low dose were 3.2 (1.2), 3.2 (1.8) and 3.3 (1.2), respectively (values not significant). One patient (6%, 95% CI 0% to 17%) developed a persistent flare that subsided after increasing infliximab doses and one patient stopped infliximab because of a lupus-like reaction. In all other patients (n = 16) lowering infliximab resulted in unaltered disease activity. Infliximab levels showed that most patients had either low- (<1 mg/litre) or high (>5 mg/litre) serum trough levels. Anti-infliximab antibodies were detected in four patients.
Conclusion: Infliximab dosages of 5 mg/kg can be lowered in the majority of patients with RA using DAS28-guided dose titration without increase of disease activity. Lowering the dose of infliximab should be considered in every patient receiving higher doses infliximab.
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Infliximab is a chimeric monoclonal antibody that binds with high affinity and specificity to tumour necrosis factor (TNF)α and neutralises its biological activity. Several studies in early and refractory rheumatoid arthritis (RA) demonstrate that infliximab gives rapid and sustained clinical response, delays radiographic progression and improves functional status and health-related quality of life (QOL).1–3 The adverse effects reported in clinical trials are generally mild in severity.
However, interpretation of the optimal individual dose of infliximab is not completely straightforward. Although in two pivotal randomised controlled trials (RCTs) (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE)1 and Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT))2 3 low doses tended to be less effective then higher doses, this difference was only significant in the ATTRACT study with respect to the American College of Rheumatology 50% improvement (ACR50) criteria responders and not for the primary endpoint (ACR20). Based on these studies, 17% at most of the patients seems to benefit from doses >3 mg/kg. In a recent dose escalation study 22% of the 360 patients seem to benefit from a dose >3 mg/kg.4 However, no control group without dose escalation was present in this study. Therefore, it cannot be ruled that clinical improvement was also due to the natural course of the disease instead of the dose escalation.
In conclusion, summarising available studies, it seems that doses of >3 mg/kg infliximab are only necessary in a small subset of patients.
In clinical practice, however, higher doses (based on the subjective clinical judgment of the treating doctor) are much more frequently used. Large clinical practice-based observational cohort studies show that within 1 year in 22–51% of all patients the infliximab dose was escalated.4–7 It could be postulated that a proportion of patients treated with higher doses of infliximab receive supratherapeutical doses.
A possible solution for avoiding individual overdosing of anti-TNFα could be titration of the infliximab dose based on actual disease activity scores. Previous work8 9 demonstrates that individual dose titration results in overall dose reduction while maintaining clinical efficacy. Dose titration based on the disease activity is also applied in the Behandel Strategieen (BeSt) study, a study that compared different treatment strategies in early RA.10 Although the tight dose-escalation protocol resulted in the fact that 43 patients (46%) received dose escalations, due to permanent monitoring of the disease activity 28 patients (67%) on high-dose infliximab could taper down and finally stop infliximab. Therefore titration of the infliximab dose based on disease activity could avoid over- and undertreatment.
Possible benefits of this approach include a substantial reduction in costs and possible reduction in dose-dependent side effects. The latter could be relevant in light of the recently published dose-dependant increase in solid and haematological malignancies during treatment with monoclonal anti-TNFα antibodies.11
In addition to dose titration based on disease activity, patient data derived from rheumatology and gastroenterology suggest that the determination of serum trough concentrations of infliximab and anti-infliximab antibodies may help to optimise treatment. Low serum trough levels of infliximab have been associated with reduced clinical efficacy.4 12–15 Furthermore, clinical response in RA decreases rapidly with serum infliximab trough levels under 1 mg/litre.15 Of note, in contrast to the lower limit, less is known about the upper limit of the therapeutic window.
The pharmacokinetics of infliximab can be altered by the formation of antichimeric antibodies against infliximab (human anti-chimeric antibodies (HACAs)). HACAs have been found in 8% to 43% of patients with RA treated with infliximab and have been associated with less efficacy and higher adverse event rates.15–18 Knowledge of the (anti-)infliximab serum concentrations could therefore provide auxiliary information for the decision whether a dose escalation or de-escalation is necessary.
The aim of the present study is to assess the percentage of patients with RA treated with infliximab in which dose reduction could be reached without loss of clinical efficacy and to confirm the feasibility of disease activity guided infliximab dose adjustment.
Patients with RA according to the ACR 1987 revised criteria treated at the Sint Maartenskliniek (Nijmegen, The Netherlands) with 5 mg/kg infliximab (irrespective of dose frequency) were included in this prospective cohort study.19 These patients were initially treated with 3 mg/kg, but had been subsequently dose escalated to 5 mg/kg based on the clinical judgement of the treating doctor. At each visit the patients were weighed and dosed in mg per kg bodyweight, with a maximum allowed deviation of +/−10%
Two other inclusion criteria were used: stable disease activity and stable treatment: current high disease activity (28-joint Disease Activity Score (DAS28) >5.1) was not allowed and the infliximab dose or interval was not altered within the timeframe of two infusions. No other inclusion or exclusion criteria were used. Enrolment took place from August to October 2006.
Retrospective description of the study population
A standardised chart review form was used to collect data on demographics, previous medication and clinical benefit of infliximab. Demographic data included age, gender, disease duration and rheumatoid factor results. The number of previous disease-modifying antirheumatic drugs (DMARDs) and previous biologicals was also recorded. The retrospective clinical benefit of 3 mg/kg and 5 mg/kg dose infliximab was recorded by noting DAS28 scores at the start of the initial 3 mg/kg infliximab therapy, after 14 weeks 3 mg/kg infliximab therapy, before dose escalation to 5 mg/kg, after dose escalation to 5 mg/kg and before DAS28-guided dose reduction, the start of the current study. The DAS28 scores were recorded along with the duration of therapy, the percentage of flare before dose escalation and the response after dose escalation.
Prospective DAS28-guided dose reduction
After inclusion infliximab dose was decreased to 3 mg/kg; the dosing intervals were left unaltered. Treatment with DMARDs or prednisone was allowed and was intended to remain unchanged. Patients were followed-up for at least three infusion visits by a doctor. Disease activity was evaluated immediately before each infusion using the DAS28.20 A disease flare was defined based on reversed European League Against Rheumatism (EULAR) response criteria as documented previously:8 20 an increase in DAS28 exceeding 1.2 or an increase in DAS28 exceeding 0.6 and a current DAS28 >5.1 (high disease activity). Patients were encouraged to contact the investigators if they experienced a flare of disease activity between two visits. If a flare persisted for more than 1 infusion, the dose of infliximab was again escalated, and disease activity was measured after this re-challenge. Finally, adverse events were assessed at every visit.
The primary end point was defined as the proportion of patients in whom infliximab dosages could not be lowered without inducing a persistent (>1 visit) flare of disease activity within the timeframe of two lowered dosages of infliximab. No control group was included in the design, assuming that disease activity would have remained stable in all patients when the infliximab dose would have remained stable.
Measurement of serum infliximab and anti-infliximab antibody levels
Serum samples were collected 1 h prior and directly after each infusion, for the assessment of serum infliximab and anti-infliximab antibodies. Infliximab and anti-infliximab antibody levels in serum were determined by an enzyme-linked immunosorbent assay and a radioimmunoassay respectively.17 21
We categorised serum trough levels in low (<1 mg/litre), medium (1–5 mg/litre) and high (>5 mg/litre) levels. In contrast to the lower limit, less information is available about the maximum desirable infliximab serum trough level. Therefore, we arbitrary choose that serum trough levels above 5 mg/litre are high levels, which is five times the minimum serum trough level and 3.3 times the average serum trough level.22 Previously, Wolbink et al14 used tertiles to categorise serum levels at 14 weeks in low, medium and high levels, also categorising serum trough levels above 5 mg/litre as high.
Adjusting the dosage of infliximab treatment guided by the actual disease activity was performed as routine clinical care in the Sint Maartenskliniek. Approval from the Medical Research Ethics Committee (MREC) was not necessary after consultation because DAS28-guided dose adaptation was performed as part of usual care.
Descriptive statistics were provided using mean (SD) or median (25th percentile to 75th percentile) values depending on the (non-)parametric distribution of measured variables. The disease activity at study start and at the end of the study was compared using a paired Student t test. The confidence interval around the point estimate of the percentage of patients in whom a flare occurred after dose reduction was calculated as follows: incidence rate±1.96×incidence rate×√(incidence rate×(1–incidence rate)/number of cases). Non-parametric variables were analysed using the Wilcoxon rank sum test (paired samples) and the Mann–Whitney U test (independent samples).
In August 2006, 125 patients with RA were being treated with infliximab in the Sint Maartenskliniek, of which 20 (16%) were receiving infliximab in a dose of 5 mg/kg. These patients were treated for 20 (14) months with 5 mg/kg infliximab with an infusion interval of 6.1 (1.5) weeks. These 20 patients were selected to participate in this study. Two patients dropped out before study start: one patient was switched to rituximab and another to adalimumab, both because of longstanding moderate disease activity (DAS28: 4.42 and 4.34 respectively). Baseline characteristics of the 18 patients in this study are listed in table 1.
Retrospective description of the study population
The mean DAS28 in our study population before the start of infliximab was 5.7 (1.2) In the first 14 weeks after the start of 3 mg/kg infliximab the DAS28 was decreased to 3.9 (1.3) (table 2). After a mean of 27.0 (16.1) months, dose was escalated to 5 mg/kg. The DAS28 before dose escalation was 4.8 (1.6) and decreased after dose escalation to 3.5 (1.1).
Prospective DAS28-guided dose reduction
The difference in DAS28 score between the first and the last visit was not significant (p = 0.91). The primary end point, defined as the proportion of patients in whom infliximab dosages could not be lowered without inducing a persistent (>1 visit) flare of disease activity within the timeframe of two lowered dosages of infliximab, was met in one patient (6%, 95% CI 0% to 17%). In this patient, lowering the infliximab dose resulted in an increase of >1.2 (3.30 to 4.65) in DAS28 before the second low dose infusion. This increase sustained until the next infusion (DAS28 5.11). After re-challenge with 5 mg/kg infliximab this patient responded again (DAS28 2.47). Three other patients in the infliximab group flared at the third visit. One of them had to stop infliximab because of a “lupus-like reaction”. In the other two patients the flare subsided spontaneously without medical intervention after the next visit. All other patients remained in stable disease activity after lowering the dose of infliximab. The mean DAS28 in patients without a flare was 3.32 (1.1), 3.18 (1.1) and 3.04 (1.1) before the first, second and third low dose of infliximab. Individual components of the DAS28 in patients without a flare showed the following pattern: median (25th percentile to 75th percentile) values at visits 1, 2 and 3 respectively were 1.0 (0–3), 1.0 (0–2) and 1.0 (0–3) (swollen joint count), 1.0 (0–2), 0.0 (0–3) and 1.0 (0–2) (tender joint count), 23.0 (8–40), 25.0 (11–33) and 16.0 (9–31) (erythrocyte sedimentation rate (ESR)), 27 (18–40), 22 (10–42) and 29 (20–39) (visual analogue scale (VAS)).
None of the patients contacted the investigators between visits because of experienced increased disease activity or adverse effects. In two patients, side effects (nausea and alopecia) led to a dose decrease of concomitant treatment with methotrexate.
Measurement of serum infliximab and anti-infliximab antibody levels
The median serum trough infliximab levels (interquartile range) were before the first decreased dose 4.7 (0.48–12) mg/litre. After the dose was decreased the infliximab serum trough level decreased to 3.1 (0.59–6.2) mg/litre and 3.1 (0.17–8.2) mg/litre, before the second and third 3 mg/kg infliximab infusion respectively (table 3).
Serum trough infliximab levels showed considerable variation between patients. However, the infliximab serum trough levels before dose decrease did not show a Gaussian distribution. Most patients had either low or high serum trough levels.
Detectable anti-infliximab antibodies were found in two and four patients, respectively, before and after dose decrease. These patients had significant lower serum trough levels compared to patients without detectable anti-infliximab antibodies (p<0.005, Mann–Whitney U test). Infliximab serum trough levels in the one patient with unsuccessful dose decrease were high: 12.2 mg/litre, 8.7 mg/litre and 12.7 mg/litre, before the first and second 3 mg/kg infliximab infusion and the first 5 mg/kg infusion respectively. In this patient anti-infliximab antibodies could not be detected.
Our study demonstrates that infliximab in a dose of 5 mg/kg could be down titrated to lower infliximab doses (3 mg/kg) in the great majority of patients with RA without increase of disease activity, and that this approach is feasible in clinical practice.
Although the number of patients in the present study is limited and no control group is present, this does not necessarily hamper internal validity. Firstly, a higher number of patients would only increase precision, but at present even the most conservative estimate (ie, higher border of confidence interval) of percentage of patients shows that most patients can be lowered safely without increase of disease activity. Furthermore, the best-case scenario in a control group would be stable disease activity in all patients (it seems very unlikely that patients would improve spontaneously after being stable for a long time). With the therefore conservative assumption of stable disease activity, the percentage of patients that can be down titrated is never overestimated.
There are several possible explanations for the fact that infliximab could be lowered in almost all patients. The first possibility is that infliximab serum trough levels after de-escalation are still above the minimal effective serum level. This seemed to be the case in the majority of patients in our study. This finding is interesting, as in most of our patients a documented high disease activity was present before dose escalation and clinical response was again achieved in these patients. Although this seems contradictory, the observed patterns could be explained by either regression to the mean,7 or by a temporary need for higher infliximab doses.
Another possible explanation for our findings could be already subtherapeutical infliximab serum trough levels before dose reduction. In these patients, dose de-escalation of subtherapeutical doses should of course be successful. Low serum trough levels could be caused by the production of anti-infliximab antibodies or an increased infliximab clearance, and both patterns were seen in a subset of our patients. Finally, it could be postulated that some patients have developed (secondary) resistance to anti-TNFα agents without antibodies or low serum levels of infliximab.
A few aspects regarding the generalisability of our study should be noted. Firstly, the liberal inclusion criteria enhanced external validity of the study. Furthermore, the studied subjects were included from a source population that does not differ much from other infliximab cohorts; the drug survival of all patients treated with infliximab in our cohort9 23 and the percentage of patients that receive higher doses are both lower than other biological DMARD registers.6 7 However, these more conservative characteristics of the source population would only result in an underestimation of percentage of patients with RA treated with high-dose infliximab that could be downtitrated.
In conclusion, our study indicates that a dose of 5 mg/kg infliximab could be lowered in the majority of patients with RA without persistent increase of disease activity measured with the DAS28 in routine clinical practice. Individual dose titration of infliximab should be considered in daily clinical care to reach the best individual dose, thus avoiding dose-dependant side effects and optimising cost effectiveness. Further investigation into the added value of the determination of serum infliximab concentrations is necessary to determine when therapeutic drug monitoring may help to optimise this treatment.
Competing interests: None.
Ethics approval: Approval from the Research Ethics Committee (MREC) was not necessary after consultation because dose adaptation was performed as part of usual care.