115significantly shorter in those who had detectable ATIs compared to those that did
not [ 21 , 22 ]. The impact of anti-drug antibodies has not been as profound in early
clinical trials of scheduled dosing, however. In the original ACCENT I trial of inf-
liximab in CD, an association between maintenance of clinical response and the
presence of antibodies was not appreciated [ 4 ]. Similarly, in a retrospective cohort
of 105 CD patients receiving infliximab, the presence of antibodies was not associ-
ated with decreased duration of remission, C-reactive protein (CRP) levels, or endo-
scopic improvement [ 23 ]. In a study of scheduled dosing in UC by Seow and
colleagues, ATI status was not associated with clinical response, although inconclu-
sive levels (meaning that drug was present which prevented antibodies to be mea-
sured with conventional enzyme-linked immunosorbent assays [ELISAs]) were
associated with improved mucosal healing, clinical responses, and reduced rates of
colonic resection in those with an ATI-inconclusive result [ 24 ].
The clinical impact of antibodies to adalimumab and certolizumab pegol had
also been assessed retrospectively, with conflicting results. In an observational
study by Karmiris and colleagues, there was no association between the presence of
anti-adalimumab antibodies and short-term response rates, although positive anti-
bodies were associated with lower adalimumab serum levels at 24 weeks [ 25 ]. In
both the PRECISE-2 and WELCOME trials, the presence of antibodies directed
against certolizumab pegol was also not associated with worse clinical outcomes
[ 18 , 26 ]. However, another smaller cohort study using a novel homogenous mobility
shift assay did appreciate an association between detectable antibodies and elevated
serum inflammatory markers and Crohn’s Disease Activity Index (CDAI) [ 27 ].
Interestingly, antibodies were present in 35% of patients of this cohort, demonstrat-
ing the potential influence that measurement techniques may have on the interpreta-
tion and assessment of the impact of antibodies directed against biologic therapies.
Anti-drug antibodies are also associated with an increased risk of adverse events
related to biologic therapy. Specifically, several studies have appreciated an
increased risk of infusion reactions with infliximab in the presence of antibodies to
the drug [ 5 , 21 , 23 , 24 ]. These reactions can range from headache or nausea and
vomiting to fever, rigors, or even shortness of breath or anaphylactoid reactions.
This increased risk has been appreciated in both CD and UC.
Pharmacokinetics and the Clinical Impact of Drug Levels
Serum concentrations of biologic therapies correlate strongly with the time from the
last dose, with peaks shortly after a dose is administered, followed by subsequent
declines in levels. These drug concentrations are associated with the dose adminis-
tered, although there do appear to be differences between agents. For example, inf-
liximab, which is administered intravenously, leads to much higher peaks in drug
levels than the subcutaneously administered anti-TNF agents. Also, the median
half-life of subcutaneous agents may be longer than that of infliximab [ 28 ].
Breakdown and clearance of these agents likely involve several mechanisms,
8 Therapeutic Drug Monitoring of Biologic Agents