The course of Disease Activity, infliximab serum concentrations and anti-infliximab antibody concentrations measured, between two standard infliximab infusion time- periods, in patients with rheumatoid arthritis.

Infliximab is a chimeric monoclonal antibody that binds with high affinity and
specificity to TNF-alpha and neutralizes its biological activity. Several
studies in both early as refractory rheumatoid arthritis demonstrate that
infliximab gives rapid and sustained clinical response, delays radiographic
progression, and improves functional status and health-related QOL

Despite the success of infliximab and other biological therapies, approximately
14-30% of the patients treated with infliximab fail to respond. Furthermore, in
clinical practice 22-51% of the patients with RA receive within 1 year higher
doses of infliximab. This is in contrast to the two pivotal randomised clinical
trials (ASPIRE and ATTRACT) in which at most 17% of the patients seems to
benefit from a higher dose infliximab. A higher dose of infliximab could
however increase dose dependent side effects and will increases the costs of
the therapy.

Therefore a more individualized approach is needed to tailor the
infliximab-dose. Possible solutions for avoiding individual overdosing of
antiTNF-alpha could be titration of the infliximab dose based on actual disease
activity scores. The use of DAS28 scores, as measure of disease activity, will
help to identify responders and non-responders objectively and quickly.

In addition to dose titration based on disease activity, data derived from both
rheumatology and gastro-enterology patients suggest that the determination of
serum trough concentrations of infliximab and anti-infliximab antibodies may
help to optimize treatment. Low serum trough levels of infliximab have been
associated with reduced clinical efficacy. Furthermore, clinical response in RA
decreases rapidly with serum infliximab trough levels under 1 mg/l. The
pharmacokinetics of infliximab can be altered by the formation of antichimeric
antibodies against infliximab (HACA). HACA*s have been found in 8% to 43% of RA
patients treated with infliximab and have been associated with less efficacy
and higher adverse event rates. Knowledge of the (anti-) infliximab
serum-concentrations could therefore provide auxiliary information for the
decision whether a dose escalation or de-escalation is necessary. Currently we
are conducting a cohort study to determine the added value of pharmacokinetic
parameters above disease activity guided treatment.

Although cross sectional data about the relationship between (anti)infliximab
levels and response are available, longitudinal data about the relation between
pharmacokinetics and disease activity are absent. Therefore, the right moment
to measure disease activity and serum (anti)infliximab levels is still unknown.
The most practical moment to collect disease activity and pharmacokinetic
information is just before the administration of a new course of infliximab
(trough levels). Besides practical arguments, there is also evidence that serum
trough levels are associated with reduced clinical efficacy. However, the
infusion interval of infliximab is 4-8 weeks. Therefore, it cannot be ruled out
that disease activity changes over times during the infusion course:
theoretically decreasing infliximab levels could lead to increased disease
activity.

More information is therefore needed about the course of the disease activity
between two infusions, and how disease activity is related to (anti-)infliximab
serum levels. More information is also needed about the moment of
anti-infliximab formation. Knowledge of these pharmacokinetic and
pharmacodynamic parameters could help us to determine the position of
therapeutic drug monitoring infliximab therapy in rheumatoid arthritis.

Therefore, this observational, descriptive open-label
pharmacokinetic-pharmacodynamic cohortstudy describes the relationship between
disease activity and (anti)infliximablevels in patients with rheumatoid
arthritis.

Primary Research Question:
Is the disease activity halfway through the infusion significant higher
compared to the disease activity at the start if infusion or lower compared to
the disease activity at the end of infusion?

Secundary Research Questions:
1) What's the relationship between infliximab serum levels and disease activity?

2) How progresses the anti-infliximab levels in time and how are these
anti-infliximab levels related infliximab serum levels and disease activity.

Observational, descriptive open-label pharmacokinetic-pharmacodynamic
cohortstudy

Participants of this study are patients who are already treated with infliximab
for rheumatoid arthritis, an authorized indication for infliximab. Before each
infusion, as part of the standard treatment in our hospital, DAS28-scores are
assessed and blood samples collected.

In this study one dose interval will be observed. During this interval three
additional blood samples are collected: one our after the infusion started, one
after 50% of the infusion interval and after 75% of the infusion interval. At
50% and 75% of the DAS28 score will also be assessed. Both interventions will
lead to a minimal burden or risk.