Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis

Infliximab is a chimeric monoclonal antibody against tumor necrosis factor-alpha (TNF-α) used in the treatment of rheumatoid arthritis (RA); its efficacy was demonstrated in a randomized controlled trial [1]. The variable inter-individual response is explained at least in part by individual pharmacokinetics [2]. Clinical response in RA is indeed influenced by infliximab serum concentration [2‐6], and we have recently shown that this concentration predicts long-term disease control in daily practice [7]. Adjustment of infliximab dosage for individuals may be useful in improving therapeutic response [8, 9]. Hence, patients with persistent active disease and low infliximab concentrations could benefit from an increase in infliximab dosage, whereas those with poor disease control and high infliximab concentrations should switch to another biopharmaceutical. In contrast, patients with optimal disease control and high infliximab concentrations might benefit from a controlled reduction in infliximab dose or an increase of dosing intervals to decrease the risk of dose-related side effects.

We aimed to determine whether the measurement of serum infliximab concentration modifies the therapeutic strategy and improves the control of disease activity in RA. The secondary objective was to study whether this improvement in control of disease activity is related to changes in infliximab concentration.

To our knowledge, this is the first study to highlight the usefulness of pharmacokinetic monitoring of infliximab concentration to control disease activity in RA. Indeed, the measurement of trough infliximab concentration modified the therapeutic decision for half of our patients and led to improved control of disease activity for patients for whom infliximab dosage was increased. Our results confirm those of a clinical observational study that did not monitor infliximab concentrations [8]. The strength of our approach lies in a strategy that took into account both disease activity and serum infliximab concentration.

The second important finding is the relation between increase in serum infliximab concentration and clinical improvement, as measured by the DAS28. Because concomitant medications remained unchanged during the study for patients whose infliximab dosage had been increased, the improvement in DAS28 should have resulted from the increase in infliximab concentration. Our results also confirm the inter-individual variability of infliximab pharmacokinetics. Despite a median infliximab dose (3.75 mg/kg [2.80 to 7.30]) above that recommended in patients with RA, 7 patients (29%) had low trough concentrations.

Clinicians can face two situations with RA patients receiving infliximab. The first corresponds to patients with optimal disease control, for whom the physician could consider reducing infliximab dosage. However, a decrease in infliximab dosage without infliximab concentration monitoring may lead to underexposure, a situation that can predict insufficient control of disease activity and increased risk of positivity for ATI [4, 14]. For the preliminary therapeutic decision, infliximab dosage reduction was planned for 6 patients; however, because these patients were all considered satisfactorily exposed or underexposed, they continued the same regimen for the final therapeutic decision. The second situation corresponds to patients with disease control the physician considers acceptable or inadequate. In this situation, the physician could consider increasing the infliximab dosage to improve the control of disease activity. However, concerns arise in the prolonged use of TNF-α antagonists, especially at high doses [15]. Therefore, the measurement of serum infliximab concentration in this situation could be useful to avoid an unnecessary increase in dosage in patients with concurrent high infliximab concentration and hence a risk of dose-dependent side effects. Monitoring of infliximab concentrations in this situation would lead the clinician to increase the dosage only if the patient does not have a high infliximab concentration. Therapeutic drug monitoring of infliximab could result in a lowering of dosage in patients having higher exposure than needed, in an increasing of dosage in others, or in a discontinuation of infliximab in non-responders with high exposure. As a whole, such a strategy should improve the cost-effectiveness of infliximab in RA.

Our method to determine infliximab serum concentration detects the active form of infliximab (that is, the species that can bind to TNF-α), not infliximab molecules that are already bound to TNF-α or ATI. The choice of measuring the active form allows investigators to analyze the concentration-effect relationship.

Immunogenicity induced by anti-TNF-α biopharmaceuticals has been associated with low concentrations and poor clinical outcomes [16]. Our technique for ATI detection was limited by the presence of circulating infliximab. The problem is well known and is encountered whatever the method used [17]. Also, ATI may have underestimated the infliximab determination by neutralizing both infliximab paratopes. However, such undetectable infliximab molecules are inactive and cannot be taken into account for pharmacokinetic-pharmacodynamic analysis. Positivity for ATI influences the pharmacokinetics of infliximab in ankylosing spondylitis [18] and inflammatory bowel disease [19], but the determining factor in the concentration-effect relation of infliximab is infliximab itself.

Only one patient was positive for ATI, and this can be explained by the duration of infliximab treatment, 56 months [3 to 76]. Indeed, patients positive for ATI probably had already switched to another treatment because of clinical signs of immunization or secondary failure of treatment. ATI false-negative results may have occurred for sera with detectable infliximab concentrations.

Our study has several limitations. Because it is an open-label observational study, patients may have been influenced by the therapeutic decision, especially those who were notified of an increase in infliximab dosage. Therefore, our results need to be confirmed by a randomized controlled study comparing therapeutic drug monitoring of infliximab with usual care. Also, our approach, based on a single clinical assessment, can be applied only for patients considered to have stable disease activity and not those with acute flare, whose condition requires a rapid therapeutic intervention. Because patients with acute flare were not considered in our study, we cannot extend our strategy to such patients. Because RA activity varies with time, we used a weekly diary to estimate global disease activity between two consecutive infusions to limit this factor. Another limitation of our study is that our population of RA patients had been treated for a long time with infliximab. Whether a dosage adjustment during the early initiation of treatment could be of benefit in terms of response is a challenging question. Since the concentration-effect relationship of infliximab is poorly known, therapeutic drug monitoring will be more difficult to test at treatment initiation. For that reason, our results apply only to RA patients with a relatively long period of treatment, not to patients at their initiation.

The measurement of serum trough infliximab concentration modifies the therapeutic decision for RA patients and leads to improved control of disease activity. Thus, therapeutic drug monitoring of infliximab may improve the control of disease activity in RA.