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as albumin, weight, disease activity and burden, etc., and therefore TDM will probably
be more accurate on an individual rather than population-based level. Third, levels
may need to be higher to achieve remission than to maintain remission. Fourth, with
respect to antibodies in the era of drug-tolerant assays, the phenomenon of transient
antibodies is not well understood. Fifth, assays need to be developed that differentiate
neutralizing from non-neutralizing antibodies, which may impart different clinical
effects. Sixth, more data are needed to determine whether higher drug levels are
needed to achieve remission in UC vs. CD. Seventh, although more difficult and more
invasive to obtain, it is possible that tissue drug concentrations may be more accurate
predictors of response than serum levels. Eighth, it is unknown what the upper limits
of drug levels should be and if high levels are toxic, e.g., it may be possible that high
levels could potentially be associated with a higher risk of infection, malignancy, anti-
TNF-induced psoriasiform rash, or even immune complex deposition. Finally, more
well-designed randomized studies are needed with respect to proactive TDM.
Two other injectable anti-TNFs, certolizumab pegol and golimumab, are mar-
keted for CD and UC, respectively. There are scant data with respect to TDM using
these drugs and, thus, more work needs to be done before TDM can be used effec-
tively for these. There is also a paucity of data on TDM with anti-integrin therapy,
but it is expected that TDM studies with vedolizumab will be performed in the near
future. Similar research will be needed for newer biologic agents, such as
ustekinumab, an antibody against a common subunit of both interleukin-12 and
interleukin-23, as they become available for the treatment of patients with IBD.
An additional area that will require active research is the role of TDM with further
development of biosimilars. Biosimilars are monoclonal antibodies with identical
amino acid sequences as the original compound. However, due to different produc-
tion methods or systems, as these agents are synthesized in living tissue, they may
have differences in amino acid glycosylation, phosphorylation, or other posttran-
scriptional modifications. The immunogenicity profiles of these agents remain uncer-
tain, as assays will need to be developed that measure antibodies specific to the
biosimilar but not the reference drug, specific to the reference drug but not the bio-
similar, or common to both agents [ 54 ]. Randomized controlled studies of infliximab
biosimilar CT-P13 from the rheumatologic literature that suggest efficacy and serum
concentrations may be similar to that seen with reference infliximab in patients with
rheumatoid arthritis or ankylosing spondylitis [ 55 , 56 ]. However, extrapolating these
data to IBD may be problematic due to differences in clearance, dosing, and the
inflammatory burden when compared to rheumatologic disorders [ 54 ].
Conclusion
Monoclonal antibodies directed against TNF-alpha have revolutionized medical
therapy in both CD and UC. There is a growing body of evidence demonstrating
associations between clinical outcomes and both anti-TNF serum concentrations
F.I. Scott and M.T. Osterman