Digestive Diseases and Sciences (2018) 63:761–767
Long‑Term Outcome of Iniximab Optimization for Overcoming
Immunogenicity in Patients with Inammatory Bowel Disease
· Ravy K. Vajravelu
· Mark T. Osterman
· Adam S. Cheifetz
Received: 4 September 2017 / Accepted: 6 January 2018 / Published online: 16 January 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Background Preliminary data suggest that treatment optimization can reverse immunogenicity and regain response in patients
with IBD and secondary loss of response (SLR) to anti-TNF therapy due to antidrug antibodies. However, data regarding
the long-term outcome of these patients are scarce.
Aims We aimed to investigate drug retention in IBD patients of whom inﬂiximab was optimized to overcome immunogenic-
ity and variables associated with drug retention.
Methods This was a retrospective, multicenter study of consecutive IBD patients with antibodies to inﬂiximab (ATI), based
on either proactive or reactive therapeutic drug monitoring, who underwent inﬂiximab optimization (increasing dose, short-
ening interval, adding an immunomodulator, or combination) to overcome immunogenicity from September 2012 to July
2015; they were followed through December 2015. ATI were analyzed using the drug-tolerant Prometheus homogeneous
mobility shift assay. Drug retention was deﬁned as no need for drug discontinuation due to SLR or serious adverse event.
Results Our cohort consisted of 22 patients (Crohn’s disease, n = 15). At the end of follow-up [median, (IQR): 17.3 (10.5–
32.8) months] 77% (15/22) of patients were still on drug. Univariable Cox proportional hazards regression analysis identi-
ﬁed ﬁrst detectable ATI titer as the only variable associated with drug retention (HR: 0.89; 95% CI: 0.82–0.98, p = 0.016).
Receiver-operating characteristic analysis identiﬁed an ATI titer < 8.8 U/mL associated with drug retention.
Conclusions In real-life clinical practice, optimization of inﬂiximab therapy can prevent drug discontinuation in approxi-
mately 3/4 of patients with ATI, especially in those with low titers. Large prospective studies are needed to conﬁrm these data.
Keywords Crohn’s disease · Ulcerative colitis · Therapeutic drug monitoring · Antibodies to inﬂiximab
Anti-tumor necrosis factor (TNF) therapy has revolutionized
the care of patients with inﬂammatory bowel diseases (IBD),
Crohn’s disease (CD), and ulcerative colitis (UC) . Never-
theless, up to 20% of patients receiving regular maintenance
dosing may develop antibodies to inﬂiximab (ATI) leading
to a rapid immune clearance and inadequate drug concen-
trations and subsequent secondary loss of response (SLR)
and treatment failure [2–6]. These ATI, typically present in
higher concentration, are commonly deﬁned as persistent.
In contrast, transient ATI are typically present in lower con-
centrations and do not appear to negatively aﬀect the phar-
macokinetic proﬁle of inﬂiximab and/or have a signiﬁcant
clinical impact on disease activity. Immunogenicity has also
been linked to serious infusion reactions necessitating drug
As therapeutic options for patients with moderate to
severe IBD and SLR to anti-TNF therapy are still limited,
several strategies have been applied to regain response
before changing to another biologic agent. Such approaches
include increasing of dose, shortening of infusion interval,
and/or the addition of an immunomodulator (IMM) [8–12].
Preliminary data show that anti-TNF therapy optimization
can reduce immunogenicity, increase drug concentration,
Mark T. Osterman and Adam S. Cheifetz have equally contributed
to this work.
* Konstantinos Papamichael
Division of Gastroenterology, Center for Inﬂammatory
Bowel Diseases, Beth Israel Deaconess Medical Center,
Harvard Medical School, 330 Brookline Ave., Boston,
MA 02215, USA
Division of Gastroenterology, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA